Process for preparing and drying solid rasagiline base

ABSTRACT

Disclosed is crystalline R(+)-N-propargyl-l-aminoindan containing water at an amount of less than 0.5% by weight and a pharmaceutical composition comprising the same, and the process for the manufacture and the validation thereof. Also disclosed is a process for the preparation of solid rasagiline base.

The application claims benefit of U.S. Provisional Application No.61/132,487, filed Jun. 19, 2008, the contents of which are herebyincorporated by reference.

Throughout this application various publications and published patentsare referenced. The disclosures of these publications in theirentireties are hereby incorporated by reference into this application inorder to more fully describe the state of the art to which thisinvention pertains.

BACKGROUND OF THE INVENTION

R(+)-N-propargyl-l-aminoindan (“R-PAI”), also known as rasagiline, hasbeen reported to be a selective inhibitor of the B-form of the enzymemonoamine oxidase (“MAO-B”) and is useful in treating Parkinson'sdisease and various other conditions.

Rasagiline mesylate is approved for treating Parkinson's disease eitheras monotherapy or as an adjunct with other treatments. See, e.g.AGILECT®, Physician's Desk Reference (2007), 61^(st) Edition, ThomsonHealthcare.

A synthesis of rasagiline is disclosed in U.S. Pat. No. 5,532,415 inwhich example 3 describes recovery of rasagiline base as an oil afterchromatographic separation. The other synthetic examples in U.S. Pat.No. 5,532,415 show rasagiline salt preparation from its crude form orits racemic form which is further reacted with appropriate acids to formpharmaceutically acceptable salts.

In pharmaceutical compositions, crystallinity is a desirable property inan active pharmaceutical ingredient. Crystal substance allow for ease inprocessing and formulating into most types of pharmaceutical dosageforms. Rasagiline base may be isolated in a crystalline form.

The solid rasagiline base prepared by crystallization is typically notcompletely “dry” and does contain solvent. There is a need for a methodsuitable for drying solid rasagiline base from solvent while minimizingloss of yield due to sublimation.

SUMMARY OF THE INVENTION

The subject invention provides crystalline R(+)-N-propargyl-l-aminoindancontaining water at an amount of less than 0.5% by weight.

The subject invention also provides a pharmaceutical compositioncomprising R(+)-N-propargyl-l-aminoindan containing water at an amountof 0.5% by weight and a pharmaceutically acceptable carrier.

The subject invention also provides a process for drying solidR(+)-N-propargyl-l-aminoindan comprising exposing the solidR(+)-N-propargyl-l-aminoindan to a temperature of less than 40° C. and apressure of between 2-1013.3 mbar for an amount of time suitable to drythe solid R(+)-N-propargyl-l-aminoindan.

The subject invention also provides a process for preparing apharmaceutical composition comprising crystallineR(+)-N-propargyl-l-aminoindan containing water at an amount of 0.5% byweight and a pharmaceutically acceptable carrier, comprising: a) dryingsolid R(+)-N-propargyl-l-aminoindan at a temperature of less than 40° C.and a pressure of between 2-1013.3 mbar for an amount of time suitableto dry the solid R(+)-N-propargyl-l-aminoindan; and b) combining thedried R(+)-N-propargyl-l-aminoindan recovered in step a) with thepharmaceutically acceptable carrier, thereby preparing thepharmaceutical composition.

The subject invention also provides a process for producing a validatedbatch of a drug product containing crystallineR(+)-N-propargyl-l-aminoindan and at least one pharmaceuticallyacceptable carrier for distribution comprising: a) producing a batch ofthe drug product; b) determining the water content by weight in thesample of batch; and c) validating the batch for distribution only ifthe crystalline R(+)-N-propargyl-l-aminoindan in the batch contains lessthan 0.5% water by weight.

The subject invention also provides a process for producing crystallineR(+)-N-propargyl-1-aminoindan comprising:

-   -   a) purifying a salt of R(+)-N-propargyl-1-aminoindan;    -   b) dissolving the purified salt of R(+)-N-propargyl-1-aminoindan        in water to form a solution;    -   c) cooling said solution to a temperature of 0-15° C.;    -   d) basifying said solution to a pH of 9.5-12.5 to form a        suspension; and    -   e) separating said crystalline rasagiline        R(+)-N-propargyl-1-aminoindan from the suspension.

The subject invention also provides a process for producing crystallineR(+)-N-propargyl-1-aminoindan comprising:

-   -   a) obtaining a solution of R(+)-N-propargyl-1-aminoindan in a        water-soluble organic solvent;    -   b) combining the solution with water;    -   c) cooling said solution to between 0 and 20° C.    -   to form crystalline R(+)-N-propargyl-1-aminoindan;    -   d) isolating the crystalline R(+)-N-propargyl-1-aminoindan; and    -   e) repeating steps a)-d) if the amount of        S(+)-N-propargyl-1-aminoindan is more than 0.1 wt % relative to        the total amount of R(+)-N-propargyl-1-aminoindan obtained in        step d).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect of pressure on evaporation/sublimation rate ofliquid rasagiline base at 60° C.

FIG. 2 shows the effect of pressure and temperature on solid rasagilinebase sublimation rate.

FIG. 3 compares the temperature profiles of Rasagiline base preparationon small and large scales.

FIG. 4 shows the particle size and shapes of the Rasagiline Tartratebefore purification.

FIG. 5 shows the particle size and shapes of the Rasagiline Tartrateafter purification.

DETAILED DESCRIPTION OF THE INVENTION

Due to the low melting point and its ability to sublime, drying of solidrasagiline by routine techniques has been observed to result in loss ofyield.

Provided herein is a method of drying solid rasagiline base from solventunder conditions which minimize loss of yield due to sublimation.

The subject invention provides crystalline R(+)-N-propargyl-l-aminoindancontaining water at an amount of less than 0.5% by weight.

In one embodiment, the crystalline R(+)-N-propargyl-1-aminoindan containwater at an amount of no more than 0.06% by weight.

The subject invention also provides a pharmaceutical compositioncomprising R(+)-N-propargyl-l-aminoindan containing water at an amountof 0.5% by weight and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition is formulated for oraladministration. In another embodiment, the pharmaceutical composition isformulated for transdermal application. In yet another embodiment, thepharmaceutical composition is in the form of a transdermal patch.

The subject invention also provides a process for drying solidR(+)-N-propargyl-l-aminoindan comprising exposing the solidR(+)-N-propargyl-l-aminoindan to a temperature of less than 40° C. and apressure of between 2-1013.3 mbar for an amount of time suitable to drythe solid R(+)-N-propargyl-l-aminoindan.

In one embodiment, the drying chamber is heated to less than 40° C. Inanother embodiment, the drying chamber is heated to less than 35° C. Inyet another embodiment, the drying chamber is heated to less than 25° C.In yet another embodiment, the drying chamber is heated to less than 22°C.

In one embodiment, the pressure at the drying chamber is between2-1013.3 mbar. In another embodiment, the pressure at the drying chamberis between 3-500 mbar. In yet another embodiment, the pressure at thedrying chamber is between 5-250 mbar. In yet another embodiment, thepressure at the drying chamber is between 10-100 mbar. In yet anotherembodiment, the pressure at the drying chamber is between 20-50 mbar. Inyet another embodiment, the pressure at the drying chamber is between22-28 mbar. In yet another embodiment, the pressure at the dryingchamber is between 20-25 mbar. In yet another embodiment, the pressureat the drying chamber is between 2-3 mbar. In yet another embodiment,the pressure at the drying chamber is between 4-5 mbar. In yet anotherembodiment, the pressure at the drying chamber is between 2-5 mbar.

In embodiment, the drying chamber is heated to less than 40° C. and thepressure at the drying chamber is between 2-1013.25 mbar. In anotherembodiment, the drying chamber is heated to less than 35° C. and thepressure at the drying chamber is between 20-50 mbar. In yet anotherembodiment, the drying chamber is heated to less than 35° C. and thepressure at the drying chamber is between 22-28 mbar. In yet anotherembodiment, the drying chamber is heated to less than 35° C. and thepressure at the drying chamber is between 20-25 mbar. In yet anotherembodiment, the drying chamber is heated to less than 25° C. and thepressure at the drying chamber is between 22-28 mbar. In yet anotherembodiment, the drying chamber is heated to less than 25° C. and thepressure at the drying chamber is between 20-25 mbar.

In another embodiment, the amount of time for drying is at least 45hours.

By a temperature of less than 40° C., it is meant that all tenth andinteger degrees Celsius within the range are specifically disclosed aspart of the invention. Thus, 39.9, 39.8, 39.7° C., . . . , and 39, 38,37° C., . . . , and so on are disclosed as embodiments of thisinvention. Similarly, by a pressure between 2-1013.3 mbar, it is meantthat all tenth and integer percentages within the range are specificallydisclosed as part of the invention. Thus, 2.1, 2.2, 2.3 . . . 1013.2,1013.2, 1013.3 are included as embodiments of this invention.

The subject invention also provides a process for preparing apharmaceutical composition comprising crystallineR(+)-N-propargyl-l-aminoindan containing water at an amount of 0.5% byweight and a pharmaceutically acceptable carrier, comprising: a) dryingsolid R(+)-N-propargyl-l-aminoindan at a temperature of less than 40° C.and a pressure of between 2-1013.3 mbar for an amount of time suitableto dry the solid R(+)-N-propargyl-l-aminoindan; and b) combining thedried R(+)-N-propargyl-l-aminoindan recovered in step a) with thepharmaceutically acceptable carrier, thereby preparing thepharmaceutical composition.

Additional embodiments of this process are described throughout thespecification.

The subject invention also provides a process for producing a validatedbatch of a drug product containing crystallineR(+)-N-propargyl-l-aminoindan and at least one pharmaceuticallyacceptable carrier for distribution comprising: a) producing a batch ofthe drug product; b) determining the water content by weight in thesample of batch; and c) validating the batch for distribution only ifthe crystalline R(+)-N-propargyl-l-aminoindan in the batch contains lessthan 0.5% water by weight.

In one embodiment, the batch is validated only if the crystallineR(+)-N-propargyl-l-aminoindan in the batch contains less than 0.06%water by weight.

The subject invention also provides a process for producing crystallineR(+)-N-propargyl-1-aminoindan comprising:

-   -   f) purifying a salt of R(+)-N-propargyl-1-aminoindan;    -   g) dissolving the purified salt of R(+)-N-propargyl-1-aminoindan        in water to form a solution;    -   h) cooling said solution to a temperature of 0-15° C.;    -   i) basifying said solution to a pH of 9.5-12.5 to form a        suspension; and    -   j) separating said crystalline rasagiline        R(+)-N-propargyl-1-aminoindan from the suspension.

In one embodiment of the process, step a) comprises:

-   -   i) dissolving the salt of R(+)-N-propargyl-1-aminoindan in water        to form a solution;    -   ii) adding a water-soluble organic solvent to the solution;    -   iii) cooling the solution to a temperature of about 0-10° C.;        and    -   iv) obtaining the purified salt of R(+)-N-propargyl-1-aminoindan        from the suspension.

In another embodiment of the process, the purified salt ofR(+)-N-propargyl-1-aminoindan obtained in step iv) is of enhancedoptical purity relative to the R(+)-N-propargyl-1-aminoindan prior tocrystallization.

In another embodiment of the process, the salt ofR(+)-N-propargyl-1-aminoindan is a tartrate salt.

The subject invention also provides a process for producing crystallineR(+)-N-propargyl-1-aminoindan comprising:

-   -   a) obtaining a solution of R(+)-N-propargyl-1-aminoindan in a        water-soluble organic solvent;    -   b) combining the solution with water;    -   c) cooling said solution to between 0 and 20° C. to form        crystalline R(+)-N-propargyl-1-aminoindan;    -   d) isolating the crystalline R(+)-N-propargyl-1-aminoindan; and    -   e) repeating steps a)-d) if the amount of        S(+)-N-propargyl-1-aminoindan is more than 0.1 wt % relative to        the total amount of R(+)-N-propargyl-1-aminoindan obtained in        step d).

In one embodiment of the process, the water-soluble organic solvent isan alcohol.

In another embodiment of the process, the alcohol is either ethanol orisopropanol or a mixture of ethanol and isopropanol.

In another embodiment of the process, the crystallineR(+)-N-propargyl-1-aminoindan is of enhanced optical purity relative tothe R(+)-N-propargyl-1-aminoindan prior to crystallization.

As used herein, “PAI” refers to N-propargyl-1-aminoindan.

As used herein, “drug substance” refers to the active ingredient in adrug product, which provides pharmacological activity or other directeffect in the diagnosis, cure, mitigation, treatment, or prevention ofdisease, or to affect the structure of any function of the body of manor animals.

As used herein, “drug product” refers to a pharmaceutical composition infinished dosage form containing the drug substance as well as at leastone pharmaceutically acceptable carrier.

As used herein, “pharmaceutically acceptable carrier” refers to acarrier or excipient that is suitable for use with humans and/or animalswithout undue adverse side effects (such as toxicity, irritation, andallergic response) commensurate with a reasonable benefit/risk ratio.

As used herein, “stability testing” refers to tests conducted atspecific time intervals and various environmental conditions (e.g.,temperature and humidity) to see if and to what extent a drug productdegrades over its designated shelf life time. The specific conditionsand time of the tests are such that they accelerate the conditions thedrug product is expected to encounter over its shelf life.

R(+)-N-propargyl-1-aminoindan can be obtained in the crystalline formcharacterized by a powder X-ray diffraction pattern having peaks at 8.5,12.6, 16.1, and 16.9 in degrees two theta ±0.2. It can be furthercharacterized by an X-ray powder diffraction pattern having peaks at20.3, 20.9, 25.4, 26.4, and 28.3 in degrees two theta ±0.2; or by amelting point of 38-41° C.

A process for the manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises: a) dissolving a salt ofR(+)-N-propargyl-1-aminoindan in water to form a solution; b) coolingsaid solution to a temperature of about 0-15° C.; c) basifying saidsolution to a pH of about 11 to form a suspension; and d) obtaining saidcrystalline rasagiline R(+)-N-propargyl-1-aminoindan from thesuspension.

Another process for the manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises: a) obtaining a first organicsolution of liquid R(+)-N-propargyl-1-aminoindan; b) completelyevaporating the solvent from the first organic solution under vacuum toform a residue; c) dissolving the residue in a second organic solvent toform a second organic solution; d) completely evaporating the secondorganic solvent from the second organic solution under vacuum to form asecond residue; and e) maintaining the second residue at a temperaturebetween 0 and 25° C. to form crystalline R(+)-N-propargyl-1-aminoindan.

Yet another process for the manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises a) obtaining a solution ofR(+)-N-propargyl-1-aminoindan in a water-soluble organic solvent; b)combining the solution with water; c) cooling said solution to between 0and 20° C. to form crystalline R(+)-N-propargyl-1-aminoindan; and d)isolating the crystalline R(+)-N-propargyl-1-aminoindan.

Crystalline rasagiline base has lower water solubility than manyrasagiline salts, especially the mesylate salt, which is water soluble.The solubility of rasagiline mesylate in water is 92 mg/ml at a pH of6.7 and 570 mg/ml at a pH of 3.3, both measured at 25° C. At the sametemperature, the solubility of rasagiline base in water is 5.5 mg/ml ata pH of 11.

Crystalline rasagiline base may be used as a synthetic intermediate tobe used to attain a rasagiline salt, such as rasagiline mesylate orrasagiline tartrate. The crystalline rasagiline base may be dissolved ina solvent and reacted with an acid to form a pharmaceutically acceptableacid addition salt. The crystallization of rasagiline base could provideadditional purification of the acid addition salt.

Water solubility is often an important characteristic of an activepharmaceutical ingredient, especially when formulating oralcompositions. Sometimes, lipophilicity of an active pharmaceuticalingredient is desired when formulating other pharmaceuticalcompositions. Crystalline rasagiline base may be useful for formulatingpharmaceutical compositions wherein low solubility in water is desired.For example, compositions for transdermal administrations can beformulated from lipophilic compounds. Examples of such transdermalcompositions include ointments, creams and patches.

Specific examples of pharmaceutical acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described, e.g., inU.S. Pat. No. 6,126,968 to Peskin et al., issued Oct. 3, 2000.Techniques and compositions for making dosage forms useful in thepresent invention are described-in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,dicalcium phosphate, calcium sulfate, mannitol, sorbitol,microcrystalline cellulose and the like. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornstarch, natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Lubricants used in these dosage forms include sodiumoleate, sodium stearate, sodium benzoate, sodium acetate, sodiumchloride, stearic acid, sodium stearyl fumarate, talc and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, croscarmellose sodium, sodium starchglycolate and the like.

U.S. Pat. No. 6,126,968, the entire contents of which are incorporatedherein by reference, disclosed that the stability of formulationscomprising PAI can be significantly improved by the incorporation ofrelatively large amounts of certain alcohols. In particular, the alcoholis selected from the group of pentahydric or hexahydric alcohols (U.S.Pat. No. 6,126,968). The alcohol is typically selected from mannitol,xylitol or sorbitol (U.S. Pat. No. 6,126,968). The composition mayfurther comprise citric acid (U.S. Pat. No. 6,126,968).

(R)-PAI itself may be prepared, for example, according to the processdescribed in Example 6B of WO 95/11016.

Transdermal Formulations and Transdermal Patches

Transdermal Formulations are medicated adhesive patches placed on theskin to deliver a time-released dose of medication through the skin andinto the bloodstream. A wide variety of pharmaceuticals can be deliveredthrough transdermal patches, such as nicotine for smoking cessation,scopolamine for motion sickness, estrogen for menopause, and preventionof osteoporosis, nitroglycerin for angina, lidocaine for pain relieffrom shingles. Some pharmaceuticals must be combined with othersubstances, such as alcohol, to increase their ability to penetrate theskin. Molecules of insulin, and many other pharmaceuticals, however, aretoo large to pass through the skin. Transdermal patches have severalimportant components, including a liner to protect the patch duringstorage, the drug, adhesive, a membrane (to control release of the drugfrom the reservoir), and a backing to protect the patch from the outerenvironment. The two most common types of transdermal patches are matrixand reservoir types. (“Transdermal Patches” Wikipedia, Nov. 15, 2007,Wikipedia Foundation, Inc., Dec. 13, 2007http://en.wikipedia.org/wiki/Transdermal_patch; and Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000)

In reservoir type patches, a drug is combined with a non-volatile,insert liquid, such as mineral oil, whereas drug in matrix type patchesa drug is dispersed in a lipophilic or hydrophilic polymer matrix suchas acrylic or vinylic polymers. Adhesive polymers, such aspolyisobutylene, are used to hold the patch in place on the skin.(Stanley Scheindlin, (2004) “Transdermal Drug Delivery: PAST PRESENT,FUTURE,” Molecular Interventions, 4:308-312).

The major limitation to transdermal drug-delivery is the intrinsicbarrier property of the skin. Penetration enhancers are often added totransdermal drug formulations in order to disrupt the skin surface andcause faster drug delivery. Typical penetration enhancers includehigh-boiling alcohols, diols, fatty acid esters, oleic acid andglyceride-based solvents, and are commonly added at a concentration ofone to 20 percent (w/w). (Melinda Hopp, “Developing Custom AdhesiveSystems for Transdermal Drug Delivery Products,” Drug Deliver)

Rasagiline may also be used in combination with other drug in atransdermal patch, such as Levodopa, L-carbidopa, beserazide,ladostigil, or riluzole.

Experimental Details—Set 1: Initial Preparation of Rasagiline Crystals

EXAMPLE 1 Isolation of Rasagiline Base by Splitting and Extraction

Rasagiline mesylate was prepared essentially as described in U.S. Pat.No. 5,532,415 example 6B, with the exception that the tartrate salt wassplit by addition of NaOH, and the rasagiline free base was isolated asan oil. The mesylate salt was then formed by addition of methanesulfonicacid.

120 g of rasagiline mesylate were dissolved in 700 ml of deionizedwater. 400 ml of toluene were added and the mixture was basified with25% NaOH solution to a pH of about 14. After stirring, two phasesseparated. The lower water phase was extracted with 200 ml of toluene.The phases were allowed to separate and the aqueous phase was discarded.

The two toluenic extractions were combined and the solvent was distilledunder vacuum. The yield of rasagiline base was 88.5 g of a yellowish oilwith a melting point of below 20° C.

25.1 g of the liquid rasagiline base was sampled. The sample was mixedwith ethanol and the solvent was distilled under vacuum. 22.6 g of therasagiline base residue, in the form of a yellowish oil remained afterthe ethanol evaporation. The rasagiline base in oil form remained in oilform for a number of weeks, and did not crystallize spontaneously.

EXAMPLE 2 Isolation of Rasagiline Base by Splitting and Extraction

155 g of rasagiline tartrate, prepared essentially as described in U.S.Pat. No. 5,532,415 example 6B, and 20 g of rasagiline mesylate, preparedas described in example 1, were dissolved in 800 ml of water. 400 ml oftoluene were added to the solution and the mixture was basified with 25%NaOH solution to a pH of about 14 and heated to 45±5° C.

After stirring, two phases were separated. The lower water phase wasextracted twice with 300 ml of toluene at 45±5° C. The organic phaseswere combined and the aqueous phase was discarded.

The combined organic phase was washed with 200 ml of deionized water.Then the solvent was distilled under vacuum and 50 ml isopropanol wereadded to the resulting residue. The solvent was removed by vacuum andadditional 50 ml isopropanol were added and then removed by vacuum. 100g of syrup-like liquid rasagiline base were formed.

EXAMPLE 3 Splitting and Spontaneous Crystallization from Water

15 g of rasagiline mesylate were dissolved in 150 ml water whilestirring. The solution was cooled to 5° C. and 25% NaOH solution wasadded slowly. During the addition, batch temperature was maintainedbetween 3 and 5° C. Solid precipitation was observed after reaching a pHof 7.5. After reaching a pH of 11, the NaOH addition was stopped, thebatch was stirred while cooling for one hour and filtered. Thefiltration proceeded quickly. The solid product was washed with water onthe filter and dried under vacuum.

8.8 g of solid dried rasagiline base were attained. The yield was 91.6%.The melting point of the solid was determined to be 38.2-38.4° C.

EXAMPLE 4 Melt Crystallization

6 g of rasagiline base liquid in syrup-like form, from example 1, aftertoluenic evaporation were dissolved in 20 ml of isopropanol. Thesolution was evaporated in a warm water bath using a rotating evaporatorunder 12 mbar vacuum until complete solvent removal. The residue wasthen dissolved in an additional 20 ml of isopropanol and the evaporationwas repeated. The resulting residue crystallized spontaneously at roomtemperature after a few hours. The solid crystalline residue wasdetermined to be rasagiline base. 5.2 g of the solid crystalline basewere attained. The yield was quantitative.

EXAMPLE 5 Addition of Rasagiline Ethanolic Solution to Water

2.4 g of rasagiline base from example 1 were dissolved in 2.4 g ofethanol. The solution was added drop-wise to 5 ml of cold (0-5° C.)water while stirring, and a white precipitate was formed during theaddition. The resulting mixture was stirred while cooling for about 30minutes and was filtered. The filtration proceeded quickly, and thesolid product was dried to constant mass under vacuum.

2.15 g of solid crystalline rasagiline were attained, with a yield of89.6%.

Analysis: Chromatographic purity by HPLC ˜100%, Assay by HPLC—99.0%.

EXAMPLE 6 Addition of Water to Rasagiline Ethanolic Solution

3 g of rasagiline base from example 1 were dissolved in 5 ml of ethanol.The solution was stirred at room temperature and 4.5 ml of water wereadded. No precipitation occurred. The resulting solution was cooled, andat 12° C. precipitation of a white material was observed. The mixturewas cooled to ˜0° C., stirred at this temperature for 30 min, andfiltered. The filtration proceeded quickly. The solid product was washedwith water on the filter and was dried under vacuum.

2.72 g of solid crystalline rasagiline were attained, with a yield of90.0%.

Analysis: Chromatographic purity by HPLC ˜100%, Assay by HPLC—100.0%.

EXAMPLE 7 Addition of Rasagiline Isopropanolic Solution to Water

8.2 g of rasagiline base from example 1 were dissolved in 10 ml ofisopropanol and the solution was stirred at room temperature. 14 ml ofwater were added. No precipitation occurred. The resulting solution wascooled, and at 17° C. precipitation of white material was observed. 20ml of deionized water were added to the mixture and the mixture wasfurther cooled to ˜0° C., stirred at this temperature for 30 min, andfiltered.

The filtration proceeded quickly. The solid product was washed withwater on the filter and dried under vacuum. 5.96 g of solid crystallinerasagiline were attained, with a yield of 72.7%.

Analysis: Chromatographic purity by HPLC ˜100%, Assay by HPLC—99.7%

EXAMPLE 8 Addition of Water to Rasagiline Isopropanolic Solution

Crop A

148 g of rasagiline base (48.0 g from example 1, and 100.0 g fromexample 2) were dissolved in 180 ml of isopropanol. The solution wascooled to 17° C. and 252 ml of deionized water were added at thistemperature. The solution was cooled to 10° C. and seeded with solidrasagiline base. Immediate crystallization was observed. 100 ml of waterwere then added to the mixture. The mixture was cooled to 1° C., stirredat this temperature for 30 min and filtered. The solid was washed on thefilter with 200 ml of water and dried under vacuum.

138.9 g of solid, crystalline rasagiline were attained, with a yield of93.8%. The melting point in an open capillary was determined to be39.0-39.2° C.

Analysis: Chromatographic purity by HPLC ˜100%, Assay by HPLC—98.5%.

Crop B

The mother liquor and washing liquor from crop A were combined, andsolid product precipitated from the mixture. Yellowish material wasseparated by filtration and dried under vacuum.

1.5 g of solid, crystalline rasagiline base were attained, with a yieldof 1.0%.

Discussion

The solid crystalline rasagiline base which was synthesized in examples3-8 was found to be of high purity.

The same melting point value (41° C. by differential scanningcalorimetry (DSC) or 38-40° C. in an open capillary) was measured forall batches of the crystalline rasagiline base. Low levels of volatiles(water and residual solvents) were found by Karl Fischer (KF) and bythermogravimetric analysis (TGA) methods. This indicated thatcrystalline rasagiline base is not hygroscopic.

Crystalline rasagiline base was found freely soluble in polar andnon-polar organic solvents—alcohols, acetone, ethyl acetate, toluene,diethyl ether, dioxane, hexane and n-heptane.

All batches of solid rasagiline base were found highly crystalline bypowder X-ray diffraction (XRD) and DSC method. Characteristic XRD andFourier Transfer Infrared (FTIR) patterns and reproducible narrowmelting range and enthalpy show the same polymorphic composition of allexperimental batches from examples 3-8. The crystal form was designatedas Form I.

The X-Ray Diffraction equipment used was a Scintag X-Ray powderdiffractometer model X'TRA, Cu-tube, solid state detector.

Sample holder: a round standard aluminum sample holder with round zerobackground quartz plate with cavity of 25 (diameter)*0.5 (dept.) mm.

Scanning parameters: Range: 2-40 degrees two-theta.

Scan mode: Continuous scan

Step size: 0.05 deg.

Rate: 5 deg./min.

The peaks of a sample prepared according to Example 4 are listed below.The most characteristic peaks are listed in bold.

Form I 8.5 12.6 16.1 16.9 20.3 20.9 25.4 26.4 28.3

FTIR analysis of the samples was performed as follows:

Equipment: Perkin Elmer Spectrum One FT-IR Spectrometer S/N 58001.

Parameters: The samples were studied in DRIFT mode. All the spectra weremeasured in 16 scans. Resolution: 4.0 cm⁻¹.

All samples of solid rasagiline base prepared in this study appear aswhite crystalline powder (with the exception of Crop B from examplewhich was isolated as a yellowish powder.) Microscopic observation showsthat the crystallization conditions strongly affect the particle sizeand morphology. Seeded crystallization provides large regularnon-aggregated crystals while spontaneous precipitation resulted information of small aggregated particles. The difference in the particlemorphology is not related to polymorphism.

The morphology and particle size of the crystalline rasagiline base fromthe examples above is shown in the table below. The morphology andparticle size was determined by microscopic observation.

Particle Size Range Example Morphology (μm) 4 Irregular particles250-1000 5 Small rods 5-50 6 Rods 30-150 7 Small aggregated rods 5-50 8Rods 250-2000

Starting Materials for Examples 9, 10 and 11:

(1) Wet Rasagiline Hemi Tartrate containing ˜10-15% residual solvent and0.7% S-isomer.

(2) Racemic RAI base, oil, PAI content—94% by HPLC.

EXAMPLE 9 Splitting and Precipitation from Isopropanol-Water, SeededEmulsion Crystallization

70.0 g of Rasagiline Tartrate salt (1) suspended in 320 ml deionizedwater at stirring. The suspension heated to 45° C. and 31 ml of 25% NaOHsolution was added with 160 ml Toluene. The mixture was stirred and theresulting emulsion was settled. Two phases were separated. The loweraqueous phase (pH=13-14) was discarded. The upper toluenic phase waswashed with 100 ml deionized water at 45° C. and settled. Lower aqueousphase (pH=9-10) was discarded.

Toluenic solution was evaporated under vacuum in evaporator, after thesolvent evaporation completion 50 ml isopropanol was added to theresidue and evaporation was continued.

After completion of the evaporation 25 ml of isopropanol was added anddistilled out under the same conditions.

The residue, oil of R-PAI base (33.9 g), was dissolved in 41 mlisopropanol.

The solution was cooled to 15° C. and 58 ml of deionized water was addedby portions in 2 hr at cooling and stirring. During the addition ofwater oily precipitate was formed. The resulting emulsion of oil inwater was stirred at 1-3° C. for one hour, no crystallization wasobserved.

The batch was seeded with crystalline Rasagiline base at 1-3° C. andimmediate exothermic crystallization took place. 50 ml of water wasadded to the resulting slurry to improve stirrability and flowability.The batch was stirred for additional 30 minutes and filtered. The solidwas washed with water and dried at room temperature under vacuum.

31.5 g of solid dry R-PAI base were attained, with a yield of 92% on oilbase. FIG. 11 is a micrograph of this rasagiline base.

Analysis: Melting point (by DSC)—40.8° C., S-isomer by HPLC 0.02%,Purity by HPLC—100%, Assay by HPLC—98%.

EXAMPLE 10 Splitting and Precipitation from Isopropanol-Water, SeededCrystallization from Solution Isopropanol-Water

100.0 g of Rasagiline Tartrate (1) was suspended in 458 ml deionizedwater, 229 ml Toluene was added and 46 ml of 25% NaOH solution wasintroduced at stirring. The mixture was heated to 45° C., stirred at 45C for 15 minutes and settled at this temperature.

Two phases were separated. The lower aqueous phase (pH=13-14) wasdiscarded, the upper toluenic phase was washed with 140 ml deionizedwater. The resulting emulsion was settled, and two phases wereseparated. The lower aqueous phase (pH=9-10) was discarded, the toluenicsolution was evaporated under vacuum in evaporator.

After the solvent evaporation completion 60 ml isopropanol was added tothe residue and evaporation was continued.

After completion of the evaporation 50 ml of isopropanol was added anddistilled out under the same conditions.

The residue, oil of R-PAI base (46.4 g), was dissolved in 56 mlisopropanol.

The solution was cooled to 16° C. and 147.5 ml of deionized water wasadded by portions in 3 hr at cooling and stirring. During the additionof water precipitation development was observed and the batch wasimmediately seeded with crystalline R-PAI base.

The resulting suspension was cooled to 2° C., stirred at thistemperature overnight and filtered. The solid was washed with water anddried at room temperature under vacuum.

48.1 g of Solid dry R-PAI base were attained, with a yield of 96% on oilbase. FIG. 12 is a micrograph of this rasagiline base.

Analysis: Melting point (by DSC)—41.3° C., S-isomer by HPLC 0.01%,Purity by HPLC—100%, Assay by HPLC—96%

EXAMPLE 11 Racemic PAI Base Crystallization (AF-8026) Precipitation fromIsopropanol-Water

51.0 g of racemic PAI base oil (2) dissolved in 50 ml isopropanol. Thesolvent was distilled out of the solution under vacuum at evaporator.

The residue (49.4 g) was dissolved in 60 ml isopropanol, stirred andcooled. 156 ml of deionized water was added by portions in 3 hr atcooling and stirring. During the addition of water oily precipitate wasformed. The batch was seeded with crystalline Rasagiline base, nocrystallization was observed.

The resulting emulsion of oil in water was stirred at 3° C. for 1 hour,no crystallization was observed.

The batch was crystallized spontaneously during stirring overnight at 1°C. The solid was filtered, but during the filtration it began to melt.At room temperature the solid product completely liquefied on the filterin 1-2 min.

The material was sampled before the melting completion.

Analysis: S-isomer by HPLC 49.4%, Assay by HPLC—87%.

Discussion

Examples 9, 10 and 11 presented above show that the ability tocrystallize at room temperature is an intrinsic property of pureRasagiline base (R-isomer). Racemic PAI base exists at room temperatureonly in liquid form, its melting point being between 1 and 18° C.(Example 11).

The Examples also show that crystallization of Rasagiline basecontaminated with S-isomer provides significant purification of thecrystallized product. Starting material containing 0.7% of S-isomer wasprocessed into solid crystalline Rasagiline base with only 0.01-0.02% ofS-isomer.

Examples 9, 10 and 11 also show the same trend in Particle Size of thecrystallized product as was described in previous Examples. The slowseeded crystallization at 10-16° C. (Example 9) provides higher particlesize of Rasagiline base than emulsion crystallization at 1-3° C.(Example 10).

Conclusions

The above experiments demonstrate varying processes for manufacturingcrystalline R(+)-N-propargyl-1-aminoindan.

The first process for manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises: a) dissolving a salt ofR(+)-N-propargyl-1-aminoindan in water to form a solution; b) coolingsaid solution to a temperature of about 0-15° C.; c) basifying saidsolution to a pH of about 11 to form a suspension; and d) obtaining saidcrystalline rasagiline R(+)-N-propargyl-1-aminoindan from thesuspension.

Another process for manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises: a) obtaining a first organicsolution of liquid R(+)-N-propargyl-1-aminoindan; b) completelyevaporating the solvent from the first organic solution under vacuum toform a residue; c) dissolving the residue in a second organic solvent toform a second organic solution; d) completely evaporating the secondorganic solvent from the second organic solution under vacuum to form aresidue; and e) maintaining the second residue at a temperature between0 and 25° C. to form crystalline R(+)-N-propargyl-1-aminoindan.

Yet another process for manufacture of crystallineR(+)-N-propargyl-1-aminoindan comprises: a) obtaining a solution ofcrystalline R(+)-N-propargyl-1-aminoindan in a water-soluble organicsolvent; b) combining the solution with water; c) cooling said solutionto between 0 and 20° C. to form crystallineR(+)-N-propargyl-1-aminoindan; and d) isolating the crystallineR(+)-N-propargyl-1-aminoindan.

The resulting crystalline R(+)-N-propargyl-1-aminoindan can becharacterized by a powder X-ray diffraction pattern having peaks at 8.5,12.6, 16.1, and 16.9 in degrees two theta ±0.2.

The crystalline rasagiline base can further be characterized by an X-raypowder diffraction pattern having peaks at 20.3, 20.9, 25.4, 26.4, and28.3 in degrees two theta ±0.2.

The crystalline rasagiline base can further be characterized by amelting point of 38-39° C. when determined in an open capillary or 41°C. when determined by differential scanning calorimetry.

However, the crystalline rasagiline base obtained using the foregoingexamples were not dry. Accordingly, further drying processing wasundertaken.

Experimental Details—Set 2: Drying of Rasagiline and Racemic PAI Base

Examples 12-24 provide sublimation rates of rasagiline base and racemicPAI base under various conditions.

Examples 25-37 provide water content and percent yield of dry productafter rasagiline base crystallization and drying.

Crystallization experiments were performed in 100 ml and 250 ml jacketedglass reactors equipped with stirrer, circulating oil bath andthermometer. Liquid additions into the reactor were performed using 25ml dropping funnel. Solid products were filtered using Büchner filterand dried in vacuum oven in glass trays.

EXAMPLE 12 Sublimation of Rasagiline Base at 2-3 mbar Pressure and 21°C. Temperature

Approximately four (4) grams of rasagiline base was introduced into thesublimation reservoir of a standard Sigma-Aldrich glass sublimationapparatus, (Cat. No. Z221171-1EA) with internal diameter of 3 cm. Theapparatus was equipped with vacuum pump, vacuumeter and circulatingice-water bath for cooling of the apparatus' sublimation head. Theapparatus was then closed and circulation of coolant at 0 to 1° C. wasstarted. The vacuum was then built to a pressure (“P”) of 2-3 mbar andthe reservoir was introduced into thermostatic water bath maintained attemperature (“T”) of 21° C.

The process was controlled by visual observation of the sublimed solidforming on the sublimation head. After sublimation completed theoperation time was recorded, the apparatus was opened and the sublimedsolid was removed from the head and weighed.

The mean sublimation rate was calculated as follows:

Mean sublimation rate R_(s1):

R _(s1) =m/M·t [g g⁻¹ hr⁻¹]

Mean sublimation rate R_(s2):

R _(s2) =m/S·t [g m ⁻² hr⁻¹]

Mean relative sublimation rate R:

R=m·100/M·t [%/hr]

m—mass of sublimed material, g

M=mass of starting material, g

t=sublimation time, hrs

S=sublimation area (apparatus section area), m²

After 8 hours, 10 mg of sublimed rasagiline were attained, with a yieldof 0.25%. The mean sublimation rates were R_(s1)=3.12×10⁻⁵ g g⁻¹ hr⁻¹;R_(s2)=1.333 g m⁻² hr⁻¹; and R=0.0312%/hr.

EXAMPLE 13 Sublimation of Rasagiline Base at 2-3 mbar Pressure and 35°C. Temperature

The experimental steps from Example 1 was used with the exception thatT=35° C.

After 5.33 hours, 25 mg of sublimed rasagiline were attained, with ayield of 0.62%. The mean sublimation rates were R_(s1)=1.17×10⁻³ g g⁻¹hr⁻¹; R_(s2)=4.978 g m⁻² hr⁻¹; and R=0.116%/hr.

EXAMPLE 14 Sublimation of Rasagiline Base at 2-3 mbar Pressure and 60°C. Temperature

The experimental steps from Example 1 was used with the exception thatT=60° C. At 60° C., starting rasagiline was liquid (melt).

After 4.0 hours, 890 mg of sublimed rasagiline were attained, with ayield of 22.4%. The mean sublimation rates were R_(s1)=5.62×10⁻² g g⁻¹hr⁻¹; R_(s2)=236.19 g m⁻² hr⁻¹; and R=5.6%/hr.

EXAMPLE 15 Sublimation of Rasagiline Base at 20 mbar Pressure and 21° C.Temperature

The experimental steps from Example 1 was used with the exception thatP=20 mbar.

After 8.5 hours, 0 mg of sublimed rasagiline were attained, with a yieldof 0.0%. The mean sublimation rates were R_(s1)=0.0 g g⁻¹ hr⁻¹;R_(s2)=0.0 g m⁻² hr⁻¹; and R=0.0%/hr.

EXAMPLE 16 Sublimation of Rasagiline Base at 40 mbar Pressure and 21° C.Temperature

The experimental steps from Example 1 was used with the exception thatP=40 mbar.

After 8.5 hours, 0 mg of sublimed rasagiline were attained, with a yieldof 0.0%. The mean sublimation rates were R_(s1)=0.0 g g⁻¹ hr⁻¹;R_(s2)=0.0 g m⁻² hr⁻¹; and R=0.0%/hr.

EXAMPLE 17 Sublimation of Rasagiline Base at 40 mbar Pressure and 35° C.Temperature

The experimental steps from Example 1 was used with the exception thatT=35° C. and P=40 mbar.

After 5.33 hours, 8 mg of sublimed rasagiline were attained, with ayield of 0.20%. The mean sublimation rates were R_(s1)=3.75×10⁻⁴ g g⁻¹hr⁻¹; R_(s2)=1.593 g m⁻² hr⁻¹; and R=0.0375%/hr.

EXAMPLE 18 Sublimation of Rasagiline Base at 20 mbar Pressure and 35° C.Temperature

The experimental steps from Example 1 was used with the exception thatT=35° C. and P=20 mbar.

After 5.33 hours, 11 mg of sublimed rasagiline were attained, with ayield of 0.27%. The mean sublimation rates were R_(s1)=5.15×10⁻⁴ g g⁻¹hr⁻¹; R₂=2.192 g m⁻² hr⁻¹; and R=0.0506%/hr.

EXAMPLE 19 Sublimation of Rasagiline Base at 40 mbar Pressure and 60° C.Temperature

The experimental steps from Example 1 was used with the exception thatT=60° C. and P=40 mbar. At 60° C., starting rasagiline was liquid(melt).

After 5.33 hours, 25 mg of sublimed rasagiline were attained, with ayield of 0.62%. The mean sublimation rates were R_(s1)=1.17×10⁻³ g g⁻¹hr⁻¹; R_(s2)=4.978 g m⁻² hr⁻¹; and R=0.116%/hr.

EXAMPLE 20 Sublimation of Rasagiline Base at 20 mbar Pressure and 60° C.Temperature

The experimental steps from Example 1 was used with the exception thatT=60° C. and P=20 mbar. At 60° C., starting rasagiline was liquid(melt).

After 5.33 hours, 162 mg of sublimed rasagiline were attained, with ayield of 4.1%. The mean sublimation rates were R_(s1)=7.64×10⁻³ g g⁻¹hr⁻¹; R_(s2)=32.26 g m⁻² hr⁻¹; and R=0.769%/hr.

EXAMPLE 21 Sublimation of Racemic PAI Oil at 20 mbar Pressure and 22° C.Temperature

The experimental steps from Example 1 was used with the exception thatthe starting material is racemic PAI oil, T=22° C., and P=20 mbar.

After 8 hours, 0 mg of sublimed racemic PAI were attained, with a yieldof 0.0%. The mean sublimation rates were R_(s1)=0.0 g g⁻¹ hr⁻¹;R_(s2)=0.0 g m⁻² hr⁻¹; and R=0.0%/hr.

EXAMPLE 22 Sublimation of Racemic PAI Oil at 20 mbar Pressure and 35° C.Temperature

The experimental steps from Example 1 was used with the exception thatthe starting material is racemic PAI oil, T=35° C., and P=20 mbar.

After 5.33 hours, 0 mg of sublimed racemic PAI were attained, with ayield of 0.0%. The mean sublimation rates were R_(s1)=0.0 g g⁻¹ hr⁻¹;R_(s2)=0.0 g m⁻² hr⁻¹; and R=0.0%/hr.

EXAMPLE 23 Sublimation of Racemic PAI Oil at 2-3 mbar Pressure and 22°C. Temperature

The experimental steps from Example 1 was used with the exception thatthe starting material is racemic PAI oil and T=22° C.

After 3.0 hours, 10 mg of sublimed racemic PAI were attained, with ayield of 0.25%. The mean sublimation rates were R_(s1)=8.33×10⁻⁴ g g⁻¹hr⁻¹; R_(s2)=3.537 g m⁻² hr⁻¹; and R=0.08%/hr.

EXAMPLE 24 Sublimation of Racemic PAI Oil at 2-3 mbar Pressure and 60°C. Temperature

The experimental steps from Example 1 was used with the exception thatthe starting material is racemic PAI oil and T=60° C.

After 1.3 hours, 130 mg of sublimed racemic PAI were attained, with ayield of 3.25%. The mean sublimation rates were R_(s1)=2.50×10⁻² g g⁻¹hr⁻¹; R_(s2)=101.16 g m⁻² hr⁻¹; and R=2.5%/hr.

EXAMPLE 25 Addition of Water to Rasagiline Base Solution in Ethanol

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. Themixture was settled, the aqueous layer (pH>11) was separated, andorganic phase was washed with water and evaporated under vacuum inrotary evaporator. Then 30 ml absolute ethanol was added to the residueand evaporated.

Addition of absolute ethanol and solvent evaporation under vacuum wasrepeated.

The residue—15.4 g of oil was dissolved in 19.5 ml absolute ethanol atstirring.

The ethanolic solution was stirred and 27 ml water was added at 18-20°C., then the batch was seeded with crystals of solid rasagiline base.Immediate crystallization was observed. The batch was cooled to 10-15°C. and additional 11 ml water was added.

Then the batch was cooled to 0-5° C., stirred at this temperature for 30minutes and filtered. The solid was washed on the filter with 30 ml ofwater.

Wet solid (16.0 g) was dried at temperature 25° C. and reduced pressure(4-5 mbar) to constant weight. Water content of the dry product wasdetermined by the Karl Fischer (KF) method.

Water content by KF=0.18%.

Dry product=14.0 g, yield=90.9%.

EXAMPLE 26 Addition of Water to Rasagiline Base Solution in IPA

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml isopropanol was added to the residue and evaporated.

Addition of isopropanol and solvent evaporation under vacuum wasrepeated.

The residue—16.0 g of oil was dissolved in 19.5 ml isopropanol atstirring.

The solution was stirred and 27 ml water was added at 18-20° C., thenthe batch was seeded with crystals of solid rasagiline base. Immediatecrystallization was observed. The batch was cooled to 10-15° C. andadditional 11 ml water was added.

Then the batch was cooled to 0-5° C., stirred at this temperature for 30minutes and filtered. The solid was washed on the filter with 30 ml ofwater.

Wet solid (16.9 g) was dried at temperature 25° C. and reduced pressure(4-5 mbar) to constant weight. Water content of the dry product wasdetermined by the Karl Fischer (KF) method.

Water content by KF=0.21%.

Dry product=14.8 g, yield=92.5%.

EXAMPLE 27 Addition of Rasagiline Base (Oil) to IPA-Water

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml isopropanol was added to the residue and evaporated.

Addition of isopropanol and solvent evaporation under vacuum wasrepeated.

The residue—16.0 g of oil was added to isopropanol-water solution (20:27ml) at cooling and stirring. During the addition the oil, thetemperature was maintained above 40° C. in order to prevent spontaneouscrystallization of the free base.

Isopropanol-water solution temperature was maintained within 0-5° C.After addition completion, the mixture was stirred at this temperaturefor 30 minutes and filtered. The solid was washed on the filter with 30ml of water.

Wet solid (16.8 g) was dried at 25° C. and reduced pressure (4-5 mbar)to constant weight. Water content of the dry product was determined bythe Karl Fischer (KF) method.

Water content by KF=0.06%.

Dry product=13.9 g, yield=86.7%.

EXAMPLE 28 Addition of Rasagiline Base (Oil) to Cold Water

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml isopropanol was added to the residue and evaporated.

Addition of isopropanol and solvent evaporation under vacuum wasrepeated.

The residue—16.0 g of oil was added to 60 ml of cold water (0-5° C.) atcooling and stirring. During the addition the batch the temperature wasmaintained below 5° C. After the addition completion the dropping funnelwas rinsed with 6 ml of isopropanol and the rinse was introduced intothe reactor. Resulting suspension was stirred at 0-5° C. for 30 minutesand filtered.

Significant amount of solid product was found deposed on the stirrer andon the reactor surface, poor slurry homogeneity and flowability werealso observed.

The solid product was washed on the filter with 30 ml of water.

Wet solid (15.3 g) was dried at 25° C. and reduced pressure (4-5 mbar)to constant weight. Water content of the dry product was determined bythe Karl Fischer (KF) method.

Water content by KF=0.10%.

Dry product=14.1 g, yield=88.2%.

EXAMPLE 29 Addition of Rasagiline Base Solution in Ethanol to Water

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (75:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of absolute ethanol was added to the residue and evaporated.

Addition of ethanol and solvent evaporation under vacuum was repeated.

The residue—16.0 g of oil was mixed with 10 ml absolute ethanol and thenadded to cold water (0° C., T_(j)=−4° C.) at cooling and stirring.During the addition the batch temperature of 0° C. was maintained.

After the addition completion the dropping funnel was rinsed with 5 mlof absolute ethanol and the rinse was introduced into the reactor.Resulting suspension was stirred at 0° C. for 30 minutes and filtered.

Significant amount of solid product was found deposed on the stirrer andon the reactor surface, poor slurry homogeneity and flowability werealso observed. The solid was washed on the filter with 30 ml of water.

Wet solid (16.0 g) was dried at 25° C. and reduced pressure (4-5 mbar)to constant weight. Water content of the dry product was determined bythe Karl Fischer (KF) method.

Water content by KF=0.06%.

Dry product=14.1 g, yield=88.2%.

EXAMPLE 30 Addition of Water to Rasagiline Base Solution in Ethanol,Spiking with AI and PAI

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of absolute ethanol was added to the residue and evaporated.

Addition of ethanol and solvent evaporation under vacuum was repeated.

The residue—16.0 g of oil was mixed with 40 ml absolute ethanol, 1 gracemic PAI base (B.N. 2499800407) and 0.5 g Aminoindan (B.N.2500300104).

The solvent was distilled out of the resulting solution under vacuum anda 1.5 g sample (Sample 1) was taken from 17.5 g of the residue.

Then the residue (16.0 g) was dissolved in 20 ml absolute ethanol. Water(27 ml) was added to the ethanolic solution for 10 minutes at coolingand stirring. During the addition the batch temperature of 17-18° C. wasmaintained.

After the addition completion the solution was seeded with solidrasagiline base and crystallization took place. Then additional 11 ml ofwater was introduced into the reactor. Resulting suspension was cooled,stirred at 1-2° C. for 30 minutes and filtered. The solid was washed onthe filter with 30 ml of water.

Wet solid (16.1 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight.

Dry product=14.2 g, yield=88.7%.

EXAMPLE 31 Addition of Water to Rasagiline Base Solution in IPA

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of IPA was added to the residue and evaporated.

Then the residue (15.9 g) was dissolved in 19.5 ml of IPA. Water (27.2ml) was added to the solution for 10 minutes at cooling and stirring.During the addition the batch temperature of 14-19° C. was maintained.

After the addition completion the solution was seeded with solidrasagiline base and crystallization took place. Additional 11 ml ofwater was introduced into the reactor. Resulting suspension was cooled,stirred at 1-2° C. for 30 minutes and filtered. The solid was washed onthe filter with 30 ml of water.

Wet solid (15.5 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.20%.

Dry product=14.9 g, yield=93.7%.

EXAMPLE 32 Addition of Water to Rasagiline Base Solution in Ethanol

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of ethanol was added to the residue and evaporated.

Then the residue (15.9 g) was dissolved in 19.5 ml of ethanol. Water(27.2 ml) was added to the solution for 10 minutes at cooling andstirring. During the addition the batch temperature of 14-18.5° C. wasmaintained. The batch was cooled to 12° C. (T_(j)=10° C.) and seededwith solid rasagiline base. Immediate crystallization took place. Thenadditional 11 ml of water was introduced into the reactor, resultingsuspension was cooled, stirred at 1-2° C. for 30 minutes and filtered.The solid was washed on the filter with 30 ml of water.

Wet solid (17.0 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.17%.

Dry product=15.0 g, yield=94.3%.

EXAMPLE 33 Addition of Water to Rasagiline Base Solution in Ethanol,Spiking with AI and PAI

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of absolute ethanol was added to the residue and evaporated.

Addition of ethanol and solvent evaporation under vacuum was repeated.

The residue—16.0 g of oil was mixed with 40 ml absolute ethanol, 0.5 gracemic PAI base (B.N. 2499800407) and 0.25 g Aminoindan (B.N.2500300104).

The solvent was distilled out of the resulting solution under vacuum anda 0.75 g sample (Sample 1) was taken from 16.75 g of the residue.

Then the residue (16.0 g) was dissolved in 20 ml absolute ethanol. Water(27 ml) was added to the ethanolic solution for 10 minutes at coolingand stirring. During the addition the batch temperature of 17° C. wasmaintained.

After the addition completion the solution was seeded with solidrasagiline base and crystallization took place. Then additional 11 ml ofwater was introduced into the reactor. Resulting suspension was cooled,stirred at 1-2° C. for 30 minutes and filtered. The solid was washed onthe filter with 30 ml of water.

Wet solid (16.5 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.21%.

Dry product=14.9 g, yield=93.1%.

EXAMPLE 34 Addition of Water to Rasagiline Base Solution in Ethanol

Approximately twenty-three grams (20.13 g) of dry rasagiline tartratereacted with NaOH (20 g 25% solution) in water-toluene mixture (73:95ml) at stirring. The mixture was settled, the aqueous layer wasseparated, and organic phase was washed with water and evaporated undervacuum in rotary evaporator. Then 30 ml of ethanol was added to theresidue and evaporated.

Then the residue (13.9 g) was dissolved in 19.5 ml of ethanol. Water(27.2 ml) was added to the solution for 10 minutes at cooling andstirring. During the addition the batch temperature of 17° C. wasmaintained. The batch was seeded with solid rasagiline base andimmediate crystallization took place. Then additional 11 ml of water wasintroduced into the reactor, resulting suspension was cooled, stirred at1-2° C. for 30 minutes and filtered. The solid was washed on the filterwith 30 ml of water.

Wet solid (15.4 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. (Sample 2) Water content of thedry product was determined by the Karl Fischer (KF) method.

Water content by KF=0.14%.

Dry product=13.1 g, yield=94.2%.

EXAMPLE 35 Addition of Water to Rasagiline Base Solution in Ethanol

Twenty-six (26) grams of dry rasagiline tartrate reacted with NaOH (20 g25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of ethanol was added to the residue and evaporated.

Then the residue (17.9 g) was dissolved in 19.5 ml of ethanol. Water(27.2 ml) was added to the solution for 10 minutes at cooling andstirring. During the addition the batch temperature of 19° C. wasmaintained. The batch was cooled to 13° C. and seeded with solidrasagiline base. Immediate crystallization took place. Then additional11 ml of water was introduced into the reactor, resulting suspension wascooled, stirred at 1-2° C. for 30 minutes and filtered. Some solidproduct deposition on the reactor wall was observed. The solid waswashed on the filter with 30 ml of water.

Wet solid (19.9 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.18%.

Dry product=17.1 g, yield=95.5%.

EXAMPLE 36 Addition of Water to Rasagiline Base Solution in Ethanol

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of ethanol was added to the residue and evaporated.

Then the residue (15.9 g) was dissolved in 16 ml of ethanol. Water (27.2ml) was added to the solution for 10 minutes at cooling and stirring.During the addition the batch temperature of 14-19° C. was maintained.The batch was cooled to 13° C. (T_(j)=10° C.) and seeded with solidrasagiline base. Immediate crystallization took place. Then additional11 ml of water was introduced into the reactor, resulting suspension wascooled, stirred at 1-2° C. for 30 minutes and filtered. The solid waswashed on the filter with 30 ml of water.

Wet solid (17.3 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.18%.

Dry product=15.2 g, yield=95.6%.

EXAMPLE 37 Addition of Water to Rasagiline Base Solution in Ethanol

Twenty-three (23) grams of dry rasagiline tartrate reacted with NaOH (20g 25% solution) in water-toluene mixture (73:95 ml) at stirring. Themixture was settled, the aqueous layer was separated, and organic phasewas washed with water and evaporated under vacuum in rotary evaporator.Then 30 ml of ethanol was added to the residue and evaporated.

Then the residue (16.0 g) was dissolved in 19.5 ml of ethanol. Water (25ml) was added to the solution for 10 minutes at cooling and stirring.During the addition the batch temperature of 17° C. was maintained. Thebatch was cooled to 13° C. (T_(j)=10° C.) and seeded with solidrasagiline base. Immediate crystallization took place. Then additional25 ml of water was introduced into the reactor, resulting suspension wascooled, stirred at 1-2° C. for 30 minutes and filtered. The solid waswashed on the filter with 30 ml of water.

Wet solid (19.3 g) was dried at ambient temperature under reducedpressure (25 mbar) to constant weight. Water content of the dry productwas determined by the Karl Fischer (KF) method.

Water content by KF=0.22%.

Dry product=15.1 g, yield=94.4%.

Summary of Results

The starting material (solid rasagiline base, melt rasagiline base, orracemic PAI), the sublimation conditions, the yield after sublimation,and the mean sublimation rates of examples 1-13 are listed in Table 1below.

The parameters and conditions for crystallization and drying ofrasagiline base, the water content of the dried product, and thepercentage yield of the drying process in examples 14-26 are summarizedin Table 2.

TABLE 1 Effect of process parameters on PAI sublimation rates Startingmaterial Sublimation conditions Sublimed solid Mean sublimation rateExperiment Weight Pressure Temp. Time weight fraction R_(s1) R_(s2) RGA- Compound g mbar ° C. hr mg %* g/g/hr g/hr/m² %/hr −log R_(s1) 12Solid R-PAI 4.0 2-3 21 8.0 10 0.25 3.12 10⁻⁵ 1.333 0.0312 4.5  13 SolidR-PAI 3.99 2-3 35 5.33 25 0.62 1.17 10⁻³ 4.978 0.116 2.93 14 Melt R-PAI3.965 2-3 60 4.0 890 22.4 5.62 10⁻² 236.19 5.6 1.25 15 Solid R-PAI 4.020 21 8.5 0 0.0 0.0 0.0 0.0 — 16 Solid R-PAI 4.0 40 21 8.5 0 0.0 0.0 0.00.0 — 17 Solid R-PAI 4.0 40 35 5.33 8 0.20 3.75 10⁻⁴ 1.593 0.0375 3.4218 Solid R-PAI 3.992 20 35 5.33 11 0.27 5.15 10⁻⁴ 2.192 0.0506 3.29 19Melt R-PAI 4.0 40 60 5.33 25 0.62 1.17 10⁻³ 4.978 0.116 2.93 20 MeltR-PAI 3.975 20 60 5.33 162 4.1 7.64 10⁻³ 32.26 0.769 2.12 21 Rac.PAI oil4.0 20 22 8.0 0 0.0 0.0 0.0 0.0 — 22 Rac.PAI oil 4.0 20 35 5.33 0 0.00.0 0.0 0.0 — 23 Rac.PAI oil 4.0 2-3 22 3.0 10 0.25 8.33 10⁻⁴ 3.537 0.083.08 24 Rac.PAI oil 4.0 2-3 60 1.3 130 3.25 2.50 10⁻² 101.16 2.5 1.60

TABLE 2 Crystallization and drying process parameters SolventCrystallization Drying Drying Water Experiment Ratio, Water ratio,temperature, conditions conditions content by Dry product No. Type ml/gbase ml/g base ° C. mbar ° C. KF (%) yield % 25 EtOH 1.27 2.46 18-20 4-525 0.18 90.9 26 IPA 1.27 2.46 18-20 4-5 25 0.21 92.5 27 IPA 1.25 1.690-5 4-5 25 0.06 86.7 28 No 0 3.75 0-5 4-5 25 0.10 88.2 29 EtOH 1.25 3.75 0 4-5 25 0.06 88.2 30 EtOH 1.25 2.38 17-18 25 RT N/A 88.7 31 IPA 1.232.40 14-19 25 RT 0.20 93.7 32 EtOH 1.23 2.40   17-18.5 25 RT 0.17 94.333 EtOH 1.25 2.40 17 25 RT 0.21¹ 93.1 34 EtOH 1.40 2.75 17 25 RT 0.1494.2 35 EtOH 1.09 2.13 17 25 RT 0.18 95.5 36 EtOH 1.00 2.40 17 25 RT0.18 95.6 37 EtOH 1.22 3.12   17-18.5 25 RT 0.22 94.4 ¹Sample 2 only

Discussion

The data show that rasagiline base and racemic PAI base have similarsublimation ability, i.e., the sublimation rates of the R-isomer andracemic mixture are similar.

Effects of vacuum and temperature on sublimation rate of rasagiline baseand racemic PAI base are represented graphically on FIG. 1 and FIG. 2.

The figures demonstrate that at high vacuum (pressure less than 3 mbar)and elevated temperatures (60° C. and higher), high sublimation rate wasobserved.

The figures also demonstrate that at moderate vacuum (pressure higherthan 20 mbar) and low temperatures (less than 22° C.), zero sublimationrate was observed.

The figures further demonstrate that at a temperature of between 0° C.and 20° C. and a pressure of between 4-25 mbar, dried rasagilinecontains between 0.06-0.22% water by weight, and the dry product yieldis between 86.7%-95.6% by weight.

Conclusions

Moderate vacuum (pressure higher than 20 mbar) and low temperatures(less than 35° C.) could be recommended as conditions for drying ofsolid rasagiline base from solvent after crystallization.

Experimental Details—Set 3: Drying and Purifying of Rasagiline Base

Wet Rasagiline Tartrate was used for the production of Rasagiline basewhich contained 27.8% of isopropanol.

1. The Production Process

A number of processes for manufacture of rasagiline solid base aredescribed in PCT International Application Publication No. WO2008/076348, the content of which is hereby incorporated by reference.One batch was manufactured according to the production processdescribed.

1.1. The process

EXAMPLE 38 Preparation of Rasagiline Base Solid—Large Scale

The production process included the following operations:

-   -   a. Splitting of wet Rasagiline Tartrate with NaOH:

-   -   b. Isolation of free Rasagiline base as oil-like product;    -   c. Dissolution of Rasagiline base in Ethanol and seeding induced        crystallization of the Rasagiline base by water addition;    -   d. Filtration and wash of the solid product; and    -   e. Drying of the solid Rasagiline base.

Since Rasagiline base is low melting material it is processed in to theDrug Product without milling.

Process parameters and conditions are summarized in Tables 1.1-1.3below.

TABLE 1.1 Process parameters for Rasagiline base production - Tartratesplitting and Rasagiline base isolation steps Process parameters: UnitAmount Amount of Rasagiline Tartrate (starting material) Wet kg 9.5 Drykg 6.86 Total amount of 25% NaOH solution kg 7.0 pH after basification13 Reactor temperature during the basification ° C. 41-47 and splittingDuration of the basification, splitting and wash hrs 3.5 TolueneDuration hrs 3.3 evaporation End of evaporation ° C. 60 temperature Endof evaporation pressure mmHg 38 Ethanol Duration hrs 1.6 evaporation Endof evaporation ° C. 60 temperature End of evaporation pressure mmHg 44Rasagiline Duration min 27 base oil Reactor temperature (T_(r)) ° C.30-40 dissolution Filtration Duration min 4 + 1 (0.2μ) and wash Solutiontemperature ° C. 35-40

TABLE 1.2 Process parameters or Rasagiline base production - Rasagilinebase crystallization steps Process parameters: Unit Amount Ethanolicsolution Duration hrs 7.7 holding Solution temperature* ° C. 10-22Amount of water introduced prior to kg 2.3 seeding %** 19.2 Seeding andTemperature, (T_(r)) ° C. 14 breeding Stirrer speed rpm 112 Duration hrs2 Water Temperature, (T_(r)) ° C. 11-12 addition Duration min 66 CoolingEnd temperature, (T_(r)) ° C. 4 Stirrer speed rpm 112-177 Duration min95 Batch stirring Duration min 36 prior to filtration Temperature,(T_(r)) ° C. 3-4 **percent on total volume of added water

TABLE 1.3 Process parameters for Solid Rasagiline base isolation -filtration, washing, drying Process parameters: Unit Amount Filtrationand cake purging time Min. 7 Washing time (two washes) Min. 1 + 1 DryingPressure mmHg 23-30 Temperature (T_(j)) ° C. 23-35 Agitator speed rpm 8Duration (agitated) hrs 48 (34) Water in dry product by K.F. % 0.05 Dryproduct yield, % calculated on dry kg 3.7 starting Rasagiline Tartrate %77.7

1.2. Results and Discussion

During the production of the batch, there were two technical problemsrelated to large scale processing—spontaneous crystallization ofRasagiline base oil and ineffective drying of solid product.

In addition to the above mentioned two issues, the content of S-isomerin the drug substance was 0.35%, which is much higher than thespecification level (NMT. 0.1%).

These three issues are discussed below in details.

1.2.1. Crystallization and Dissolution of Rasagiline Base Oil

Isolated Rasagiline base oil between the operations step 1.2 and 1.3 wasstored in the reactor under nitrogen at cooling overnight. The basesolidified forming a block in the bottom part of the reactor. The solidglass like mass of Rasagiline base was dissolved in absolute ethanol inmore than 2 hours.

The proposed solution of this problem was to prevent the solidificationof Rasagiline base oil by holding its solution in ethanol between theoperations 2 and 3. Laboratory simulation experiments were performed inorder to evaluate the effect of this process change on yield and purityof crystallized product.

1.2.1.1. Laboratory Scale Simulation

Two batches of Rasagiline base were prepared in order to simulate thestorage of Rasagiline base in ethanol solution at differenttemperatures.

The experiments and the results are detailed below:

EXAMPLE 39 Rasagiline Base Oil Hold in Ethanol Solution for 48 hrs atCooling (7-8° C.)

17.0 g of Rasagiline base oil was dissolved in 17 g absolute ethanol.The resulting solution was introduced into refrigerator and stored at7-8° C. for 48 hrs. The ethanol solution was sampled. (sample 1).

The clear solution was then introduced into 100 ml jacketed glassreactor equipped with a stirrer, thermometer and circulating oil bath.

The reactor was cooled (T_(j)=11° C.) and 8 g of water was introduced atstirring. Then the solution was seeded with solid Rasagiline base andcrystallization was observed. The batch was stirred for 15 min at 11-12°C. and then 33.8 g of water was added. The resulting suspension wascooled to 4° C. and stirred at 1-4° C. for 30 min. The solid wasfiltered and washed twice with 17 ml water. Wet solid product (17.6 g)was dried under vacuum.

Dry product—15.7 g

Crystallization yield—92%

Analysis:

Sample 1 (Solution):

Purity by HPLC:

S-isomer—0.77%

IDD—1-Aminoindan—L.T. 0.05% (QL)

Dry Product:

Color—White to off-white

Assay—99.5%

IDD—N.D.

S-isomer—0.01%

m.p.—39.5-40.4° C.

Water content by K.F.—0.2% wt.

EXAMPLE 40 Rasagiline Base Oil Hold in Ethanol Solution for 48 hrs atAmbient Temperature

17.0 g of Rasagiline base oil was dissolved in 17 g absolute ethanol.The resulting solution was stored at ambient temperature (20-28° C.) for48 hrs. The ethanol solution was sampled (sample 1).

The clear solution was then introduced into 100 ml jacketed glassreactor equipped with stirrer, thermometer and circulating oil bath.

The reactor was cooled (T_(j)=11° C.) and 8 g of water was introduced atstirring. Then the solution was seeded with solid Rasagiline base andcrystallization was observed. The batch was stirred for 20 min at 11-12°C. and then 33.8 g water was added. The resulting suspension was cooledto 4° C. and stirred at 1-4° C. for 30 min. The batch was filtered andwashed twice with 17 ml water. Wet solid product (18.2 g) was driedunder vacuum.

Dry product—15.9 g

Crystallization yield—93.5%

Analysis:

Sample 1 (Solution):

Color—Yellowish

Purity by HPLC:

S-isomer—0.76%

IDD—1-Aminoindan—L.T. 0.05% (QL)

Dry Product:

Assay—99.9%

IDD—N.D.

S-isomer—0.01%

Melting range—39.6-40.6° C.

Water content by K.F.—0.1% wt.

1.2.1.2. Results, Discussion and Conclusion

The data presented above demonstrate that holding of Rasagiline base asethanol solution for 48 hrs in air prior to crystallization do notaffect the yield and quality of solid product. Crystalline Rasagilinebase prepared from the solution stored at low temperature (7-8° C.) hasthe same purity as the product prepared from the solution stored at roomtemperature.

As a result, rasagiline base between the isolation and crystallizationoperation should be held in ethanol solution. This operation modeprevents spontaneous crystallization of Rasagiline base oil and problemswith its dissolution.

1.2.2. Drying

Wet Rasagiline base was dried under vacuum (23-30 mm Hg) at ambienttemperature (23° C.) with no stirring for 14 hours with any results. Thesolid remained wet and contained 28% water.

After 14 hours of static drying the cake was stirred (8 rpm) and thedryer jacket was gradually heated to 35° C. during 9 hours. At this stepthe drying rate was increased significantly—the cake was sampled andonly 15% of water was found in the solid.

The drying was continued under the same conditions for additional 17hours (overnight). Then the cake was sampled and found dry (0.07% ofwater).

Additional 8 hours of drying had no significant effect on watercontent—0.05% of water was found in the next sample.

The drying regime mentioned above (P<35 mm Hg; T_(j)=35° C. and stirring8 rpm) was found effective for Rasagiline base.

1.2.3. Solid Uniformity

In the above drying process, the Drug Substance (DS) is homogenized byprolonged stirring during the drying operation. A special samplingprogram was prepared and performed during the production in order toprove the homogeneity and uniformity of the DS after the drying.

Dry Rasagiline base was sampled 5 times from different zones of thedryer. Additional 6^(th) sample was prepared by mixing of the materialsfrom each of the 5 sample. These six samples were analyzed for watercontent, assay, purity, melting point, s-isomer content and particlesize distribution. The results of analysis are shown in Table 2.1. Thedata show uniformity of the dry product.

TABLE 2.1 Rasagiline base samples analysis results Sample: 01-1 01-201-3 01-4 01-5 Mix Color Off-white Off-white Off-white Off-whiteOff-white Off-white S-isomer, % 0.36 0.36 0.32 0.35 0.35 >0.1 (OOS) IDD,(%) N.D. N.D. N.D. N.D. N.D. N.D. (>0.02) (>0.02) >0.02) ( (>0.02)(>0.02) (>0.02) Assay by 99.9 100.7 99.7 99.9 100.1 99.0 HPLC, % Waterby 0.05 0.04 0.05 0.05 0.04 0.04 K.F., % Melting 38.7-39.7 38.8-40.038.8-39.4 38.8-39.5 38.8-39.8 N.A. range, ° C. PSD by Malvern, Micronsd(0.1) 242.5 236.8 249.8 239.9 249.3 235.3 d(0.5) 549.0 539.4 562.1543.3 557.6 531.6 d(0.9) 1124.4 1121.1 1148.8 1111.3 1117.2 1076.7Morphology 1 1 1 1 1 1 group

The data in the above table demonstrate that the dryer provideseffective homogenization of 3.5 kg batch of Rasagiline base.

1.2.4. S-Isomer in Solid Product

The data presented in Table 2.1 demonstrate high level of S-isomer (OOS)found in the batch of Rasagiline base.

The data were found surprising because the typical S-isomer level in thecrystalline base was below 0.1%. In small scale rasagiline base preparedcontained 0.02-0.03% of this impurity. The level of 0.35% of S-isomer inthe crystallization product could be obtained using a starting materialhaving more than 2% of this impurity.

1.2.4.1. Simulation of the Crystallization

The difference in processing time is illustrated by comparison oftemperature profiles of pilot and laboratory batches on FIG. 3.

Crystallization of small scale normally takes about 2.5 hours, but thelarge scale was processed during 6.5 hours. The effect of processingtime on optical purification was studied in the following experiments.

EXAMPLE 41 Rasagiline Base Preparation

100 g of wet Rasagiline Tartrate was mixed with 160 ml water atstirring. 63 g of 25% NaOH solution and 200 g toluene were added to themixture, the batch was stirred for 1 hour at 40-50° C. (pH=13) and thensettled at this temperature for 0.5 hour. Lower aqueous phase wasseparated and discarded and 100 ml of water was added to the batch. Thenthe mixture was stirred for 0.5 hour and settled for 0.5 hour at 40-50°.Lower aqueous phase was separated and discarded. Upper organic phase wasevaporated on rotary evaporator under vacuum. Temperature profile of theevaporation was the same as in the pilot batch—total evaporation timewas 3 hrs 20 min, the residue was exposed to temperature 55° C. during 1hr 20 min and to 60° C. during 2 hrs.

After evaporation of toluene 75 g of absolute ethanol was added to theresidue and the evaporation was continued. Total evaporation time was 2hrs 40 min, the residue was exposed during the evaporation totemperature 55° C. and then to 60° C.

Residual product—oil of Rasagiline base (52 g) was cooled and stored at5° C. overnight. Then the base was dissolved in 52 g of absolute ethanolat stirring and 24 ml of water was added. Then the resulting clearsolution was cooled to 12.5° C. and seeded with crystalline Rasagilinebase. The crystallizing batch was stirred at 11-12° C. for 2 hours. 103g of water was introduced dropwise during one hour at cooling then thebatch was cooled to 4° C. during 1 hour 45 min and stirred at 1-4° C.for 30 min.

One half of the batch was withdrawn out of crystallizer and filtered.The solid was washed with 50 ml of water and dried under vacuum. Dryproduct (26.2 g) and filtrate (mother liquor) were sampled—Samples 4(solid) and 2 (M.L.)

The second half of the batch was stirred at cooling (1° C.) overnight,total holding time at T<4° C. was 14 hrs. Then this half batch wasfiltered, the solid was washed with 50 ml water and dried under vacuum.Dry product (17.8 g) and filtrate (mother liquor) were sampled—Samples 7(solid) and 5 (M.L.)

Analysis:

Solids:

Sample 4:

S-isomer—N.D.

Assay by HPLC—99.4%

Purity by HPLC (IDD)—N.D.

Melting range—39.8-40.5° C.

Sample 7:

S-isomer—N.D.

Assay by HPLC—99.5%

Purity by HPLC (IDD)—N.D.

Melting range—39.5-40.7° C.

Mother Liquors:

Sample 2:

S-isomer—31.3%

Rasagiline concentration by HPLC—5.8 mg/ml

Purity by HPLC (IDD)—1-Aminoindan—1.37%; RRT=1.47−0.03%; RRT=1.60−0.05%;1-Indanone—0.15%, RRT=7.8−0.07%

Sample 5:

S-isomer—26.9%

Rasagiline concentration by HPLC—6.8 mg/ml

Purity by HPLC (IDD)—1-Aminoindan—1.17%; RRT=1.47−0.03%; RRT=1.60−0.04%;1-Indanone—0.13%

1.2.4.2. Results, Discussion and Conclusion

Level of S-isomer in Rasagiline base prepared using prolongedcrystallization (14 hours, Sample 7) was undetectable. The same level ofthis impurity was found in the product crystallized during 1 hour(Sample 4).

In Table 3.1 composition of mother liquors of the small scaleexperiments is compared to the mother liquor of a large batch. Table 3.1shows that purity profiles of the mother liquor in the simulationexperiments are very similar to the large scale batch. At the same timeconcentration of S-isomer in large scale mother liquor is about 3 timeslower than in the small scale experiments.

TABLE 3.1 Composition of laboratory and pilot mother liquors ofRasagiline base crystallization Example Example No. 41 - No. 41 -Example Sample 5 Sample 2 No. 38 Holding at T < 4° C. hrs 14 1 1 S -isomer % 26.9 31.3 9.7 Rasagiline base mg/ml 6.8 5.8 7.9 conc. IDD: RRT= 0.45 % area N.D. 0.02 N.D. 1-AI 1.17 1.37 0.93 RRT = 1.5 0.03 0.03N.D. RRT = 1.6 0.04 0.05 0.05 1-Indanone 0.13 0.15 0.02 RRT = 7.8 N.D.0.07 2.06

The data show that the racemization of R-isomer of Rasagiline base doesnot take place under the large scale process conditions. The results ofsimulation experiment show that processing time has no effect on opticalpurification of Rasagiline base.

Two possible solutions for the S-isomer problem:

i) Re-crystallization of S-isomer contaminated Rasagiline base; and

ii) Additional optical purification of starting material—RasagilineTartrate.

These two approaches were studied on both small scale and large scalefor the production of Rasagiline base Drug Substance. The study isdescribed in the following sections.

2. Optical Purification of Rasagiline Base

2.1. Re-Crystallization of Rasagiline Base—Small Scale

Rasagiline base with 0.35% of S-isomer from the rejected pilot batch255500208 was re-crystallized in the laboratory using the samecrystallization procedure as was used on pilot scale.

EXAMPLE 42 Rasagiline Base Re-Crystallization

49.5 g of Rasagiline base introduced into 0.5 liter jacketed glassreactor with 52 g of absolute ethanol. The batch was stirred and heated(T_(j)=35° C.) until complete dissolution of the solid.

The solution was cooled and 24 g of water was added at stirring. Theresulting clear solution was seeded at 12° C. with solid Rasagiline baseand stirred at 11-12° C. for one hour. Crystallization was observed onthis step.

103 g of water was added at cooling and stirring during 20 minutes thenthe batch was cooled to 4° C. and stirred at 2-4° C. for 45 minutes.

The batch was cooled, the solid washed with 2×50 ml water and driedunder vacuum to constant weight.

The solid product (45.5 g) was sampled (Sample 1)

Filtrate (combined Mother Liquor and washes) was evaporated under vacuumin rotary evaporator. The oily evaporation residue (1.1 g) was sampled(Sample 2) and subjected to analysis with the solid product.

Analysis:

Solid:

Sample 1:

S-isomer—N.D.

Assay by HPLC—98.8%

Purity by HPLC (IDD)—3PAIO—L.T. 0.05% (QL); 1-Aminoindan—L.T. 0.05%(QL); 1-Indanone—L.T. 0.05% (QL) Melting range—39.1-39.8° C.

Mother Liquor:

Sample 2 (Residue after Evaporation):

Assay by HPLC—91.3%

S-isomer—7.8%

Purity by HPLC (IDD)—3PAIO—L.T. 0.05% (QL); 1-Aminoindan—0.2%;RRT=0.92−0.08%; RRT=1.62−0.13%; RRT=2.27−0.05%; 1-Indanone—L.T. 0.05%(QL); RRT=6.6−0.1%; Total IDD—0.5%

2.2. Discussion and Conclusions

The experiment detailed above demonstrates the possibility of completeseparation of S-isomer from Rasagiline base having 0.35% of thisimpurity. This result is in accordance with our previous findings ofoptical purification on laboratory scale.

3. Purification of Rasagiline Tartrate

3.1. General Considerations

Crystallization of Rasagiline salts as Rasagiline Tartrate could resultin complete separation of S-isomer from the Tartrate. PurifiedRasagiline Tartrate with very low level of S-isomer could be convertedinto Rasagiline base with almost zero content of this impurity witheffect on the optical purity in a large scale batch.

Study of Rasagiline Tartrate re-crystallization was performed in orderto evaluate the possibility of additional optical purification of thisintermediate.

3.2. Re-Crystallization of Rasagiline Tartrate

3.2.1. Procedure Evaluation

Rasagiline Tartrate crystallization experiments were performed in 0.5liter jacketed glass reactors equipped with stirrer, circulating oilbath for heating and cooling, condenser and thermometer. Vacuum oven wasused for solid drying.

Starting material with 0.7% of S-isomer was used in all experiments.Solid and liquid products were analyzed for IDD and S-isomer by HPLC.

EXAMPLE 43 Crystallization from 8 Volumes of Water

50.0 g of Rasagiline Tartrate was introduced into reactor, 300 ml ofwater was added, the mixture was stirred and heated (T_(j)=85° C.), at72° C. complete dissolution of solids was observed.

The reactor was cooled slowly and seeded with Rasagiline Tartrate at 63°C. Then crystallization was observed and the reactor was cooled to 20°C. during 2 hrs. After stirring for 30 min at 20° C. the batch wasfiltered, the solid washed with 30 ml water and dried under vacuum at50° C. to constant mass.

Wet solid—36.9 g

Dry solid—26.6 g

Yield—70.9%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.01% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

Mother Liquor:

S-isomer—2.48% area

1-Aminoindan—0.26% area, IDD—RRT=1.96−0.01% area; RRT=2.29−0.02% areaagainst the main peak of Rasagiline

EXAMPLE 44 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Water

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater, the mixture was stirred and heated (T_(j)=85° C.), to 75° C., nodissolution of solids was observed.

The resulting slurry was stirred at 75° C. for 90 minutes and cooled to12° C. during 40 min. After stirring for 40 min at 10-12° C. the batchwas filtered, the solid washed with 40 ml water and dried under vacuumat 50° C. to constant mass.

Wet solid—38.4 g

Dry solid—26.7 g

Yield—71.1%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.11% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

Mother Liquor:

S-isomer—2.62% area

1-Aminoindan—0.35% area, IDD—RRT=1.96−0.02% area—against the main peakof Rasagiline

EXAMPLE 45 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Water,Crop B Precipitation with Anti-Solvent

Crop A:

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofpre-heated water (T_(j)=85° C.), the mixture was stirred and heated, to75° C., no dissolution of solids was observed. The resulting slurry wasstirred at 75-77° C. for 90 minutes and cooled to 7° C. during one hour.After stirring for 40 min at 5-7° C. the batch was filtered, the solidwashed with 75 ml water and dried under vacuum at 50° C. to constantmass.

Wet solid—40.5 g

Dry solid—30.7 g

Yield—81.9%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.11% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

Mother Liquor:

S-isomer—4.47%

1-Aminoindan—0.62% area; IDD—RRT=1.96−0.06% area—against the main peakof Rasagiline

Crop B:

Mother Liquor from Crop A filtration divided on two equal portions (70ml each)

1^(st) Portion, Precipitation with Isopropanol

Mother Liquor cooled to 7° C. at stirring, 20 ml IPA was added, solidprecipitation observed. The suspension was stirred at 5-7° C. for 30 minand filtered. The solid washed with IPA and dried under vacuum at 50° C.to constant mass.

Wet solid—0.9 g

Dry solid—0.7 g

Yield—1.9%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.15% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

Mother Liquor:

S-isomer—8.36% area

1-Aminoindan—1.14% area; IDD—RRT=0.37−0.02% area; RRT=0.79−0.01% area;RRT=1.32−0.01% area; RRT=1.40−0.02% area; RRT=1.88−0.03% area;RRT=1.96−0.11% area—against the main peak of Rasagiline

2^(nd) Portion, Precipitation with Ethanol

Mother Liquor cooled to 7° C. at stirring, 20 ml Ethanol was added,solid precipitation observed. The suspension was stirred at 5-7° C. for30 min and filtered. The solid washed with Ethanol and dried undervacuum at 50° C. to constant mass.

Wet solid—0.9 g

Dry solid—0.6 g

Yield—1.6%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.07% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

Mother Liquor:

S-isomer—6.76% area

1-Aminoindan—0.93% area; IDD—RRT=0.37−0.01% area; RRT=0.79−0.02% area;RRT=1.32−0.01% area; RRT=1.96−0.08% area—against the main peak ofRasagiline

EXAMPLE 46 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=85° C.), to 75° C., nodissolution of solids was observed. The resulting slurry was stirred at77-79° C. for 90 minutes and then cooled to 25° C. 40 ml of IPA wasadded and the batch was cooled to 5° C. After stirring for 30 min at 5°C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

wet solid—47.9 g

Dry solid—35.9 g

Yield—95.7%

Analysis:

Solid:

Appearance—White solid

S-isomer—0.07% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

TABLE 4.1 Rasagiline Tartrate re-crystallization Example No.: 45 43 44(crop A) 46 Purification Crystallization Slurry Slurry Slurry procedurefrom solution to slurry to slurry to slurry Water to g/g 8 4 4 4Tartrate ratio (on dry basis) Anti-solvent ml/ml — — — IPA (ratio to(0.27) water) Cooling ° C. 20 12 7 5 temperature Washing ml/g WaterWater Water IPA dry 1.1 1.5 2.4 0.8 solid Pure Tartrate % 70.9 71.1 81.995.7 yield (on dry basis) S-isomer content: In Tartrate % 0.01 0.11 0.110.07 In Mother area 2.48 2.62 4.47 N.A. Liquor 1-Aminoindan content: InTartrate % wt. L.T. L.T. L.T. N.A. In mother % 0.08 0.08 0.08 liquorarea 0.26 0.35 0.62 N.A

The results in the above Table 4.1 show that re-crystallization ofRasagiline Tartrate from 4 volumes of water in slurry-to-slurry regimeis very effective providing good yield and high optical purity.Additional work was performed in order to optimize the method and toevaluate the effect of process parameters on Rasagiline Tartratepurification.

3.2.2. Process Parameterization

The following examples were performed to study the effect of mostimportant process parameters on yield and purity of re-crystallizedRasagiline Tartrate.

EXAMPLE 47 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=100° C.

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=100° C.), to 90° C.,dissolution of most of the solid was observed. The resulting slurry wasstirred at 90° C. for 90 minutes and then cooled to 25° C. 40 ml of IPAwas added and the batch was cooled to 5° C. After stirring for 30 min at5° C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

Wet solid—57.7 g

Dry solid—37.9 g

Yield—93.7% (calculated according to starting material L.O.D.=20%)

Analysis:

Solid:

Appearance—White solid

S-isomer—0.01% area

IDD—no additional peaks detected

1-Aminoindan—N.D.

EXAMPLE 48 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=65° C.

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=65° C.), to 63° C., nodissolution of solids was observed. The resulting slurry was stirred at63-64° C. for 90 minutes and then cooled to 25° C. 40 ml of IPA wasadded and the batch was cooled to 5° C. After stirring for 30 min at 5°C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

Wet solid—55.0 g

Dry solid—37.7 g

Yield—94.5%

Analysis:

Solid:

Appearance—white solid

S-isomer—0.32% area

1-Aminoindan<0.08% by HPLC against analytical standard IDD—no additionalpeaks detected

EXAMPLE 49 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=85° C., Stirring Time—15 min

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=85° C.), to 75° C.,dissolution of most of the solid was observed. The resulting slurry wasstirred at 75° C. for 15 minutes and then cooled to 25° C. 40 ml of IPAwas added and the batch was cooled to 5° C. After stirring for 30 min at5° C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

Wet solid—55.0 g

Dry solid—37.5 g

Yield—93.7% (calculated according to starting material L.O.D.=20%)

Analysis:

Solid:

Appearance—White solid

S-isomer—0.19% area

IDD—no additional peaks detected

1-Aminoindan—N.D.

EXAMPLE 50 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=85° C., Stirring Time—150 min

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=85° C.), to 75° C.,dissolution of most of the solid was observed. The resulting slurry wasstirred at 75° C. for 150 minutes and then cooled to 25° C. 40 ml of IPAwas added and the batch was cooled to 5° C. After stirring for 30 min at5° C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

Wet solid—51.9 g

Dry solid—38.4 g

Yield—96.0% (calculated according to starting material L.O.D.=20%)

Analysis:

Solid:

Appearance—White solid

S-isomer—0.10% area

IDD—no additional peaks detected

1-Aminoindan—N.D.

EXAMPLE 51 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=85° C., 100 ml of IPA

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=85° C.), to 75° C.,dissolution of most of the solid was observed. The resulting slurry wasstirred at 75° C. for 90 minutes and then cooled to 25° C. 100 ml of IPAwas added and the batch was cooled to 5° C. After stirring for 30 min at5° C. the batch was filtered, the solid washed with 30 ml IPA and driedunder vacuum at 50° C. to constant mass.

Wet solid—50.2 g

Dry solid—37.7 g

Yield—93.2% (calculated according to starting material L.O.D.=20%)

Analysis:

Solid:

Appearance—White solid

S-isomer—0.10% area

IDD—no additional peaks detected

1-Aminoindan—N.D.

EXAMPLE 52 Slurry-to-Slurry Re-Crystallization from 4 Volumes of Waterand Isopropanol, T_(j)=85° C., Prolonged Cooling Time

50.0 g of Rasagiline Tartrate was introduced into reactor with 150 ml ofwater. The mixture was stirred and heated (T_(j)=85° C.), to 75° C.,dissolution of most of the solid was observed. The resulting slurry wasstirred at 75° C. for 90 minutes and then cooled to 25° C. 40 ml of IPAwas added and the batch was cooled to 2° C. After stirring for 12 hoursat 1-2° C. the batch was filtered, the solid washed with 30 ml IPA anddried under vacuum at 50° C. to constant mass.

Wet solid—52.5 g

Dry solid—38.1 g

Yield—95.2% (calculated according to starting material L.O.D.=20%)

Analysis:

Solid:

Appearance—white solid

S-isomer—0.05% area

IDD—no additional peaks detected

1-Aminoindan—N.D.

The results of parameterization experiments are summarized below inTable 5. The data show that re-crystallization process parameter asprocessing time and temperature have strong effect on Tartrate opticalpurification.

TABLE 5.1 Effect of process parameters on Rasagiline Tartratepurification Re- crystallization Cooling S- IDD, Example temperature, °C. Time Time, Yield isomer (AI) No. T_(j) T_(r) min hrs % % (%) 47 10090 90 0.5 93.7 0.01 N.D. 48 65 63 90 0.5 94.5 0.32 L.T. 0.08 49 85 75 150.5 93.7 0.19 N.D. 50 85 75 150 0.5 96.0 0.10 N.D. 51 85 75 90 0.5 93.20.10 N.D. 52 85 75 90 12 95.2 0.05 N.D.

Decrease of re-crystallization temperature from 75° C. to 63° C. andre-crystallization time from 90 to 15 minutes causes significantincrease of S-isomer level in the solid product. At the same time nosignificant effect of the process parameters on the Yield was observed.

FIG. 4 shows that during the re-crystallization of the Tartrate saltsignificant change in the solid morphology take place. RasagilineTartrate crystallized from isopropanol or any other organic solvent hasneedle-like crystal habit.

As shown in FIGS. 4 and 5, the needle-like crystals of startingRasagiline Tartrate are transformed to rod-shaped crystals ofre-crystallized product.

3.3. Purification of Rasagiline Tartrate on Large Scale

Two batches of purified Rasagiline Tartrate were produced on large scaleaccording to the procedures described in Section 3.2. The process wasbased on the Example 46.

The results of the production are summarized in Tables 6.1 and 7.1below.

TABLE 6.1 Large Scale production of Rasagiline Tartrate Pure, Processparameters Process parameters: Batch 1 Batch 2 Starting RasagilineTartrate Wet Kg 10.0 10.0 Dry kg 6.97 6.97 Stirrer speed rpm 240 240Re-crystallization temperature: Start ° C. 75 75 End ° C. 80 80Re-crystallization time min 93 90 Cooling to 30° C. time min 116 121Cooling to 10° C. time min 137 141 Drying temperature ° C. 55 55 (Bath)Drying pressure: Start mm Hg 49 49 End 23 22 Drying duration hrs 15.3 15Dry product yield Kg % 6.1 6.0 87.5 86.0

TABLE 7.1 Quality of large batches of Rasagiline Tartrate Pure TestSpecification Batch 1 Batch 2 Description White solid White solid Whitesolid (SI-2000) Enantiomeric S-isomer; LT 0.3% LT 0.3% purity (limit NMT0.3% test by HPLC) Identification RT of the main Conforms Conforms (byHPLC) peak Chromatographic AI - NMT 1.5%; LT 0.08% (QL) LT 0.08% (QL)purity (by Any other - NMT L.T. 0.02 L.T. 0.02 HPLC) 0.1% L.O.D. NMT0.5% 0.04% 0.04%

4. Reprocessing of Rasagiline Base in Large Scale

The batch of Rasagiline base produced in Example 38 was reprocessed inorder to reduce the level of S-isomer from 0.35% and to fit thespecifications.

The reprocessing procedure was based on re-crystallization Example 42.High yield and good product quality were achieved. Process parameters ofthe laboratory scale and pilot reprocessing batches are compared inTable 8.1. Product quality of the laboratory and pilot batches ispresented in Table 9.1.

The data show that there is no significant effect of the process scaleon the reprocessing results. The batch was released by QC/QA and usedfor stability tests and formulation development.

TABLE 8.1 Rasagiline base re-crystallization parameters on small scaleand large scale batches Small scale Large scale Scale, kg 0.0495 3.43Batch size, starting material Solvent Ethanol:base ml/g 1.33 1.35 ratioWater:base ml/g 2.57 2.60 Percent of water % 18.9 19.0 introduced priorto seeding Seeding temperature ° C. 12 12 Cooling temperature ° C. 2-43-4 Cooling time min 45 30 Drying Dryer Glass tray in Hastelloyconditions vacuum oven agitated filter-dryer Temperature ° C. Ambient 35Pressure mbar 20 20-33 Duration hrs 16 14.6 Yield of dry Kg 0.0455 3.05product % 91.9 89.0

TABLE 9.1 Major quality parameters of small scale and large scalebatches of re-crystallized Rasagiline base Small scale Large scale ColorOff-white Off-white Enantiomeric purity % N.D. Passes (N.D.) (S-isomer)Assay by HPLC % 99.8 99.7 IDD by HPLC: % 1-Aminoindan L.T. 0.05 L.T.0.02 (Q.L.) (D.L.) 1-Indanone L.T. 0.05 L.T. 0.02 (Q.L.) (D.L.) 3-PAIOL.T. 0.05 L.T. 0.02 (Q.L.) (D.L.) Any other impurity N.D. L.T. 0.02(D.L.) Melting range ° C. 39.1-39.8 39.2-40.6

5. Production of Rasagiline Base from Purified Rasagiline Tartrate

Two large scale batches of Rasagiline base were produced with purifiedRasagiline Tartrate. In addition, Rasagiline base was held in ethanolsolution prior to crystallization during the process.

Process parameters and conditions are summarized below in Tables 10.1,10.2, and 10.3 in step-by-step order. The data presented in Tables10.1-10.3 demonstrate good process reproducibility in large scale andsalability of the production procedure.

TABLE 10.1 Process parameters or Rasagiline base production, Large scaleTartrate splitting and Rasagiline base isolation Steps Processparameters: Batch 1 Batch 2 Amount of Rasagiline kg 6.1 6.0 TartratePure (starting material) Total amount of 25% NaOH kg 5.8 5.8 solution pHafter basification 13 13 Reactor temperature during ° C. 43-49 40-50 thebasification and splitting Duration of the hrs 4 4 basification andsplitting Toluene Duration hrs 2.3 2.1 evaporation Temperature ° C.22-60 22-60 Pressure mmHg 67-43 70-43 Ethanol Duration hrs 1.5 1.3evaporation Temperature ° C. 21-60 19-60 Pressure mmHg 49 45-46Rasagiline Duration min 32 30 base oil Temperature ° C. 38 39dissolution Filtration Duration min 7 5 (0.2μ) and Temperature ° C. 3839 wash

TABLE 10.2 Process parameters or Rasagiline base production, Large scaleRasagiline base crystallization Steps Process parameters: Batch 1 Batch2 Ethanolic Duration hrs 11.6 12.8 solution Temperature ° C. 10-2 10-17* holding Amount of water introduced kg 2.0 2.0 prior to seeding %19 19 Seeding and Temperature ° C. 11-12 11-12  breeding Stirrer speedrpm 153 180 Duration min 116 67 Water Temperature ° C. 11-14 12 additionDuration min 77 60 Cooling End ° C. 6 6 temperature Stirrer speed rpm185 178 Duration min 120 78 Batch Duration min 98 60 stirringTemperature ° C. 6 5 prior to filtration *Cooling system failure duringthe overnight holding of the batch

TABLE 10.3 Process parameters or Rasagiline base production, Large scaleSolid Rasagiline base isolation - filtration, washing, drying StepsProcess parameters: Batch 1 Batch 2 Filtration and cake purging min 6 15time Washing time (two washes) min 15 17 Drying Pressure mmHg 37-2241-22 Temperature ° C. 35 35 (T_(j)) Agitator rpm 7 15 speed Durationhrs 20.2 22 Water in dry product by % 0.07 0.06 K.F. Dry product yieldkg 3.6 3.7 % 85.0 88.7

Quality data for batches of Rasagiline base produced are summarized inTables 11.1 and 11.2 below.

The data show high purity of the Rasagiline base and reproducibility ofits physical properties on pilot scale.

TABLE 11.1 Rasagiline base DS quality Batch No. Test 1 2 3 DescriptionOff-white Yellowish Off-white powder solid solid Melting range by USP °C. 39.2-40.6 39.4-40.5 39.7-40.6 Water content by %  0.08  0.07  0.03coulometric K.F. Residue on ignition by %  0.03  0.00  0.01 USP Heavymetals by USP % L.T. 0.002 L.T. 0.002 L.T. 0.002 Impurities anddegradation products by HPLC: 1-Aminoindan % L.T. 0.02 L.T. 0.02 L.T.0.02 1-Indanone L.T. 0.02 L.T. 0.02 L.T. 0.02 3-PAIO L.T. 0.02 L.T. 0.02L.T. 0.02 Any other impurity L.T. 0.02 L.T. 0.02 L.T. 0.02 Totalimpurities L.T. 0.02 L.T. 0.02 L.T. 0.02 N-(2-Chloroallyl)-1- ppm L.T. 1L.T. 1 L.T. 1 aminoindan by LC-MS (passes) (passes) (passes)Enantiomeric purity (S- % L.T. 0.1 L.T. 0.1 L.T. 0.1 isomer by HPLC)OVI/Residual Solvents: ppm Ethanol 295 205 L.T. 200 Toluene L.T. 200 250 42 Isopropanol L.T. 200 L.T. 200 L.T. 200 Assay on dry basis by %  99.7 99.9 100.2 HPLC

TABLE 11.2 Physical properties of Rasagiline base DS Batch No. Test 1 23 Powder density by USP: g/ml Bulk (BD) 0.497 0.426 0.443 Tapped (TD)0.727 0.579 0.624 Particle Size μm Distribution by Malvern: D (0.1)112.5 146.3 144.7 D (0.5) 404.1 386.9 388.1 D (0.9) 1099.4 968.6 988.6Morphology by light Rod shape Rod shape Rod shape microscope observationprime prime prime particles particles particles Group I Group I Group I

6. Intermediate Products—Time Limitations

There are three new intermediate solid products in the productionprocedure of Rasagiline base DS:

-   -   Wet Rasagiline Tartrate pure    -   Dry Rasagiline Tartrate pure    -   Wet Rasagiline base

The intermediates should be held for a long period of time between theprocess operations. A special study was performed in order to prove thestability of the materials under the storage conditions.

6.1. Small Scale Experiments

EXAMPLE 53 Stability Test for Wet Rasagiline Tartrate Pure

Rasagiline Tartrate Pure wet with isopropanol and water was stored atambient temperature (RT) in polyethylene bag. The solid was sampled,dried to constant weight and analyzed. The sampling and analysis wereperformed at time zero, than after 2 weeks and 4 weeks from time zero.The results are presented in Table 12 below.

EXAMPLE 54 Stability Test for Dried Rasagiline Tartrate Pure

A batch of dry Rasagiline Tartrate Pure produced in Example ?? wasstored at ambient temperature (RT) in polyethylene bag. The solid wassampled and analyzed at time zero, than after 2 weeks and 4 weeks fromtime zero. The results are presented in Table 12.1 below.

EXAMPLE 55 Stability Test for Wet Rasagiline Base

Rasagiline Base wet with water produced in Example ?? was stored atambient temperature (RT) in polyethylene bag inside aluminium laminatebag protected from light. The solid was sampled, dried to constantweight under vacuum and analyzed. The sampling and analysis wereperformed at time zero, than after 2 weeks and 4 weeks from zero time.The results are presented in Table 13.1 below.

TABLE 12.1 Stability tests for wet and dry Rasagiline Tartrate PureStart Material Test (t = 0) 2 weeks 4 weeks Dry Description White WhiteWhite GA-18062 solid solid solid S-isomer by HPLC % L.T. L.T. L.T. 0.3 0.3  0.3  ID by HPLC Conforms Conforms Conforms Chromatographic purityby HPLC: 1-Aminoindan % L.T. L.T. L.T. 0.03 0.03 0.03 Any other % L.T.L.T. L.T. 0.03 0.03 0.03 L.O.D. % 0.03 0.16 0.03 Wet Description WhiteWhite White RB-2087 solid solid solid S-isomer by HPLC % L.T. L.T. L.T.0.3  0.3  0.3  ID by HPLC Conforms Conforms Conforms Chromatographicpurity by HPLC: 1-Aminoindan % L.T. L.T. L.T. 0.03 0.03 0.03 Any other %L.T. L.T. L.T. 0.03 0.03 0.03 L.O.D.* % 0.01 0.05 0.04 *Samples of wetRasagiline Tartrate were dried prior to analysis

TABLE 13 Stability test for wet Rasagiline base Test Start (t = 0) 2weeks 4 weeks Description White solid White solid White solid Assay byHPLC % on 100.1 100.5 100.7 dry basis IDD by HPLC: 1-Aminoindan % L.T.0.02 L.T. 0.02 L.T. 0.02 1-Indanone % L.T. 0.02 L.T. 0.02 L.T. 0.023-PAIO % L.T. 0.02 L.T. 0.02 L.T. 0.02 Any other % L.T. 0.02 L.T. 0.02L.T. 0.02 Total % L.T. 0.02 L.T. 0.02 L.T. 0.02 ID by HPLC ConformsConforms Conforms Water content by %  0.04  0.04  0.03 CKF Enantiomeric% L.T. 0.1% L.T. 0.1% L.T. 0.1% purity by HPLC (S- (Passes) (Passes)(Passes) isomer)

6.2. Results and Discussion

The data presented in the Tables 12.1 and 13.1 shows that no changes inpurity of all solid intermediates occur during 4 weeks of storage. Allproducts conformed to the specifications after completion of 4-weeksstability test. Time limitations for the production intermediates arepresented in Table 14.1.

TABLE 14.1 Rasagiline base intermediate product - time limitationsStorage temperature, Time No. Product ° C. limitation 1 Wet RasagilineTartrate R.T. One month Pure 2 Dry Rasagiline Tartrate R.T. One monthPure 3 Wet Rasagiline base +2-+8° C. One month

1. Crystalline R(+)-N-propargyl-l-aminoindan containing water at anamount of less than 0.5% by weight.
 2. The crystallineR(+)-N-propargyl-1-aminoindan of claim 1 containing water at an amountof no more than 0.06% by weight.
 3. A pharmaceutical compositioncomprising the crystalline R(+)-N-propargyl-l-aminoindan of claim 1 anda pharmaceutically acceptable carrier.
 4. The pharmaceutical compositionof claim 3, formulated for oral administration.
 5. The pharmaceuticalcomposition of claim 3, formulated for transdermal application.
 6. Thepharmaceutical composition of claim 5 in the form of a transdermalpatch.
 7. A process for drying solid R(+)-N-propargyl-l-aminoindancomprising exposing the solid R(+)-N-propargyl-l-aminoindan to atemperature of less than 40° C. and a pressure of between 2-1013.3 mbarfor an amount of time suitable to dry the solidR(+)-N-propargyl-l-aminoindan.
 8. A process for preparing apharmaceutical composition comprising crystallineR(+)-N-propargyl-l-aminoindan containing water at an amount of 0.5% byweight and a pharmaceutically acceptable carrier, comprising: combiningthe dried R(+)-N-propargyl-l-aminoindan recovered in step a) of theprocess of claim 7 with the pharmaceutically acceptable carrier, therebypreparing the pharmaceutical composition.
 9. The process of claim 7,wherein the temperature for drying is less than 35° C.
 10. The processof claim 7, wherein the temperature for drying is less than 25° C. 11.The process of claim 7, wherein the pressure for drying is higher than20 mbar.
 12. The process of claim 7, wherein the amount of time fordrying is at least 45 hours.
 13. A process for producing a validatedbatch of a drug product containing crystallineR(+)-N-propargyl-l-aminoindan and at least one pharmaceuticallyacceptable carrier for distribution comprising: a) producing a batch ofthe drug product; b) determining the water content by weight with asample of the batch; and c) validating the batch for distribution onlyif the crystalline R(+)-N-propargyl-l-aminoindan in the batch containsless than 0.5% water by weight.
 14. The process of claim 13, wherein thebatch is validated only if the crystalline R(+)-N-propargyl-l-aminoindanin the batch contains less than 0.06% water by weight.
 15. A process forproducing crystalline R(+)-N-propargyl-1-aminoindan comprising: a)purifying a salt of R(+)-N-propargyl-1-aminoindan; b) dissolving thepurified salt of R(+)-N-propargyl-1-aminoindan in water to form asolution; c) cooling said solution to a temperature of 0-15° C.; d)basifying said solution to a pH of 9.5-12.5 to form a suspension; and e)separating said crystalline rasagiline R(+)-N-propargyl-1-aminoindanfrom the suspension.
 16. The process of claim 15, wherein step a)comprises: i) dissolving the salt of R(+)-N-propargyl-1-aminoindan inwater to form a solution; ii) adding a water-soluble organic solvent tothe solution; iii) cooling the solution to a temperature of about 0-10°C.; and iv) obtaining the purified salt of R(+)-N-propargyl-1-aminoindanfrom the suspension.
 17. The process of claim 16, wherein the purifiedsalt of R(+)-N-propargyl-1-aminoindan obtained in step iv) is ofenhanced optical purity relative to the R(+)-N-propargyl-1-aminoindanprior to crystallization.
 18. The process of claim 15, wherein the saltof R(+)-N-propargyl-1-aminoindan is a tartrate salt.
 19. A process forproducing crystalline R(+)-N-propargyl-1-aminoindan comprising: a)obtaining a solution of R(+)-N-propargyl-1-aminoindan in a water-solubleorganic solvent; b) combining the solution with water; c) cooling saidsolution to between 0 and 20° C. to form crystallineR(+)-N-propargyl-1-aminoindan; d) isolating the crystallineR(+)-N-propargyl-1-aminoindan; and e) repeating steps a)-d) if theamount of S(+)-N-propargyl-1-aminoindan is more than 0.1 wt % relativeto the total amount of R(+)-N-propargyl-1-aminoindan obtained in stepd).
 20. (canceled)
 21. (canceled)
 22. The process of claim 19, whereinthe crystalline R(+)-N-propargyl-1-aminoindan is of enhanced opticalpurity relative to the R(+)-N-propargyl-1-aminoindan prior tocrystallization.